tbuckley/cabot-search huggingface dataset:
Association of circulating DNA with recurrence in CRS-HIPEC patients with colorectal and appendiceal peritoneal carcinomatosis: Insights from a phase II randomized trial.
Authors: Anup Kasi, Raed Moh'd Taiseer Al-Rajabi, Anwaar Saeed, Weijing Sun, Joaquina Celebre Baranda, Haoran Li, Jo Wick, Sanjana Mullangi, Kenda Eberhardt, Shannon Bradbury, Rebecca Romero, Erin Carroll, Lori Barbosa, Mazin Francis Al-Kasspooles
Journal: Journal of Clinical Oncology (2024)

3598 Background: There is a need for biomarkers to guide patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in cases of peritoneal carcinomatosis from colorectal and appendiceal cancer. SigNatera is a blood-based quantitative test to detect colorectal cancer recurrence by indicating the presence of at least two altered colorectal cancer-associated genes in Circulating tumor DNA (ctDNA). We performed a correlative study to help determine if using SigNatera ctDNA would be a predictive and prognostic biomarker of recurrent cancer in patients who underwent CRS-HIPEC on a Phase II Randomized Trial Comparing Morbidity and Mortality of CRS-HIPEC using Mitomycin-C versus Melphalan for Colorectal and Appendiceal Peritoneal Carcinomatosis. Methods: 30 patients on the phase II trial had the option for consenting for the ctDNA correlative study utilizing SigNatera sponsored by Natera. Pre-op samples were collected prior to CRS-HIPEC on Day 0 and post-op samples ~2 weeks post-hospital discharge, followed by every 3 months x 2 years. The exploratory objective of the prognostic impact of ctDNA is evaluated by correlating pre-op ctDNA status and Disease-Free Survival (DFS) Results: All 30 pts that underwent ctDNA testing were treated with neoadjuvant chemotherapy prior to CRS-HIPEC. Pre-op ctDNA was negative in 20 pts (8 recurrences, median DFS = 15.9 months) and positive in 10 pts (7 recurrences, median DFS = 39.9 months), p =0.19. Of the 20 pre-op ctDNA(-) pts, 18 remained ctDNA(-) in post-op (12 recurrences, median DFS = 15.6 months) and 2 turned ctDNA(+) (0 recurrences). Of the 10 pre-op ctDNA(+) pts, 2 remained ctDNA(+) post-op (1 recurrence, median DFS = 9.5 months) and 8 turned ctDNA(-) (2 recurrences, median DFS = 39.9 months), p=0.1. Conclusions: The unexpected numerically favorable DFS in the pre-op ctDNA(+) group, in comparison to the pre-op ctDNA(-) group, challenges the utility of preop ctDNA status in guiding CRS + HIPEC decision-making. Though limited by small sample size, this finding may be likely due to the impact of post-op therapy which notably converted 10 preop ctDNA(+) pts to post-op ctDNA(-) status. Our findings warrant validation in a larger study to unravel the multifaceted factors influencing ctDNA’s prognostic value. Clinical trial information: NCT03073694 . [Table: see text]
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 45-month (mo) follow-up from CheckMate 648.
Authors: Ian Chau, Jaffer A. Ajani, Yuko Kitagawa, Jianming Xu, Lucjan S. Wyrwicz, Satoru Motoyama, Takashi Ogata, Hisato Kawakami, Chih-Hung Hsu, Antoine Adenis, Farid El Hajbi, Maria Di Bartolomeo, Maria Ignez Braghiroli, Eva Holtved, Mariela A. Blum Murphy, Raheel Nathani, Nan Hu, Yasuhiro Matsumura, Ken Kato, Yuichiro Doki
Journal: Journal of Clinical Oncology (2024)

4034 Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]
Neoadjuvant long-course chemoradiation plus PD1 blockade for locally advanced rectal cancer: Results of a phase 2, open-label, randomized controlled trial.
Authors: Yingchi Yang, Kai Pang, Guole Lin, Xinzhi Liu, Jiaolin Zhou, Yuanyuan Kong, Guangyong Chen, Xin Wang, Yingjiang Ye, Ang Li, Jiagang Han, Guoju Wu, Aiwen WU, Yi Xiao, Hongwei Yao, Zhongtao Zhang
Journal: Journal of Clinical Oncology (2024)

3611 Background: Several single-arm trials have reported pathological complete response (pCR) rates of 23-50% after combining neoadjuvant radiotherapy with immune checkpoint inhibitors in locally advanced rectal cancer (LARC). We aim to further clarify the efficacy and safety of adding PD1 inhibitors to the neoadjuvant long-course chemoradiation of LARC patients with this phase 2, randomized, controlled trial. Methods: Patients with mid-low, locally advanced rectal cancer were randomly allocated to receive neoadjuvant chemoradiation plus concurrent Tislelizumab (experiment group A), or neoadjuvant chemoradiation plus sequential Tislelizumab (experiment group B), or neoadjuvant chemoradiation only (control group). Patients of all three groups are scheduled to receive radical surgery after neoadjuvant treatment. The primary endpoint is pCR rate. Results: A total of 186 patients were enrolled. In the modified intention-to-treat population, which consist of patients having received chemoradiation and at least 1 cycle of PD1 blockade for the experiment groups and patients having received chemoradiation only for the control group, the pCR rates were 33.9% and 34.5% for experiment group A and B respectively, both significantly higher than the pCR rate of 15.5% in the control group (p=0.021 and 0.019). There were no significant differences between either one of the experiment groups and the control group regarding disease progression rate, grade 3-4 treatment-related adverse event rate and grade 3-4 surgical complication rate. Conclusions: For patients with mid-low locally advanced rectal cancer, the addition of PD1 inhibitors to neoadjuvant long-course chemoradiation, whether concurrently or sequentially, increases pCR rate, meanwhile raises no significant safety concerns. For the next step, phase 3 trials with larger sample sizes are encouraged. Clinical trial information: NCT05245474 .
A phase II, multicenter, open-label study of polyPEPI1018 in combination with atezolizumab in participants with relapsed or refractory microsatellite-stable metastatic colorectal (MSS mCRC) cancer (Oberto-301).
Authors: Joleen M. Hubbard, Daniel H. Ahn, Jeremy Clifton Jones, Mojun Zhu, Kathleen Wittenberger, Zsolt Csiszovszki, Eszter Somogyi, Orsolya Lorincz, Levente Molnar, József Tóth, Hagop Youssoufian, Eniko Rita Toke
Journal: Journal of Clinical Oncology (2024)

3594 Background: The efficacy of checkpoint inhibitor immunotherapy in MSI-H mCRC has not been replicated in MSS mCRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 shared tumor antigens which demonstrated early evidence of clinical activity in first-line MSS mCRC. Methods: Patients with MSS mCRC who have progressed on 2-3 lines of prior chemotherapy regimen received PolyPEPI1018 (1.2 mg, sc) and atezolizumab (1,200 mg, iv) Q3W until disease progression or unacceptable toxicity. The primary endpoint was safety. A Simon 2-stage design was applied. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 18 patients (66 % female) were enrolled for stage 1 of the study. Median age was 54 years (range 38–79), 50% had liver metastases and 67% received at least 3 lines of prior therapies. PD-L1 expression was &lt;1% for 85% of patients. The combination was well-tolerated; most common side effect related to treatment was Grade (Gr) 1-2 local skin reaction (n=22). Gr 2 events (n=2) at least possibly related to treatment were nausea, pyrexia and increased blood alkaline phosphatase. There were no Gr 3-5 events or study discontinuation due to treatment AE. The ORR was 0% and the DCR was 61%. The mPFS was 2.7 months (95%CI 1.4-4.0) and the mOS was not reached (95%CI 8.75 – NE months) at the data cut-off date. Ex-vivo FluoroSpot identified 13/16 subjects with robust, vaccine-specific CD8+ and/or CD4+ T cell responses detected against multiple vaccine antigens. For patients with available biopsy pairs (n=8), both the average PD-L1 expression (IC%, p=0.029) and the density of CD8+ tumor-infiltrating lymphocytes (TILs, p=0.019) were significantly increased, post-treatment. Patients with increased PFS (&gt; 12 weeks) had both higher levels of post-treatment PD-L1 (p=0.007) and TILs (p=0.016) than patients with PFS ≤ 12 weeks. Conclusions: PolyPEPI1018 in combination with atezolizumab was well-tolerated with no Grade 3 AEs observed. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immune responses to the modulation of tumor microenvironment and to improved disease control. The study did not proceed to stage 2; it is on-going for the collection of survival data. Clinical trial information: NCT05243862 .
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: Harry H. Yoon, Ken Kato, Eric Raymond, Richard Hubner, Yongqian Shu, Yueyin Pan, Yi Jiang, Jingdong Zhang, Sook Ryun Park, Takashi Kojima, Chen-Yuan Lin, Lucjan S. Wyrwicz, David Tougeron, Ryu Ishihara, Liyun Li, Hongqian Wu, Yanyan Peng, Shican Yan, Jianming Xu
Journal: Journal of Clinical Oncology (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]
A novel and uniquely designed bispecific antibody (LBL-024) against PD-L1 and 4-1BB in patients with advanced malignant tumors and neuroendocrine carcinoma: A report of safety and robust efficacy of LBL-024 monotherapy in phase I/II, first-in-human, open-label, multicenter, dose escalation/expansion study.
Authors: Ming Lu, Panpan Zhang, Suxia Luo, Jie Chen, Jianwei Yang, Zhengbo Song, Yongsheng Li, Ying Tang, Peng Zhao, Baorui Liu, Junhe Li, Sheng Hu, Zhiye Zhang, Lin Wu, Lijie Song, Xielin Feng, Yunfeng Shan, Tao Liu, Shengli Cai, Lin Shen
Journal: Journal of Clinical Oncology (2024)

4010 Background: LBL-024 blocks the immunosuppressive pathway of tumor cells by targeting PD-L1 and effectively localizes 4-1BB co-stimulation to the tumor microenvironment, to improve the anti-tumor immune response. Here we report the safety and efficacy of LBL-024 in patients with advanced malignant tumors, particularly the robust clinical benefit in extrapulmonary neuroendocrine carcinoma (EP-NEC). Methods: Patient population: Phase Ⅰ, advanced malignant tumors exhausted standard cares and phase Ⅱ, EP-NEC failed at least one line of chemotherapy. Seven dose levels of LBL-024 were evaluated (0.2, 0.8, 3.2, 6, 10, 15 and 25 mg/kg, i.v. Q3W) and 15 mg/kg was selected for phase Ⅱ. The primary endpoints were tolerability, safety and efficacy (RECIST 1.1) and the second objectives were pharmacokinetics, pharmacodynamics, and other efficacy parameters. Results: By October 31, 2023, 162 patients were enrolled (64 in phase Ⅰ, and 98 in phase Ⅱ). Tumor types include EP-NEC (46, 28.4%), NSCLC (33, 20.4%), biliary tract cancer (31, 19.1%), and other tumors (52, 32.1%). During the dose escalation stage, no DLT was observed, and the MTD was not reached. The median follow-up was 4.2 months (95%CI: 3.9, 4.9). 126 out of 162 patients (77.8%) experienced TRAEs of all grades, with 34 (21.0%) having grade ≥3 TRAEs. The most common TRAEs (≥15%) included anemia (31.5%), AST increased (30.9%), ALT increased (25.3%), and white blood cell count decreased (22.2%). Out of 146 who underwent efficacy evaluation, the ORR and DCR were 15.1% and 46.6%, respectively. Robust efficacy signals were observed in 41 patients with EP-NEC (Table 1). 6 months of DoR will be available for report in ASCO. Conclusions: LBL-024 has showed good safety profile and very promising antitumor effects in patients with advanced malignant tumors, particularly EP-NEC patients who failed at least one line of chemotherapy. The efficacy observed in EP-NEC is significantly higher than the historic reports with immunotherapy (≤10%) and chemotherapy (about 18%). The extremely robust efficacy and good safety profile support a pivotal study for accelerated development of EP-NEC, the highly unmet medical needs and deadly disease. Clinical trial information: NCT05170958 . [Table: see text]
Radiomic survival prediction with liver metastases in colorectal cancer.
Authors: Inae Park, Misuk Lee, Jeevan Shivakumar, Sungjae Park
Journal: Journal of Clinical Oncology (2024)

e15584 Background: The survival outcome of colorectal cancer depends upon staging and the presence of metastases. Nonetheless, there isn’t a reliable prediction model for overall survival (OS) specifically tailored to patients with colorectal cancer who have liver metastases. Consequently, this study aims to find radiomic features that can be utilized to predict OS of colorectal cancer with liver metastases. Methods: We utilized the Colorectal Liver Metastases data set in The Cancer Imaging Archive (TCIA). Overall, 197 patients with colorectal cancer metastatic to the liver were identified. Semi-automatic segmentation of liver metastases was used to extract radiomic features including Gray-Level Co-occurrence (glcm), Gray-Level Run Length Matrix (glrlm), Gray-Level Size Zone Matrix (glszm), Gray-Level Dependence Matrix (gldm), and Neighborhood Gray-Tone Difference Matrix (ngtdm). 3D Slicer was used to extract radiomic features. We tested a Cox proportional hazards model in each radiomics feature to predict OS. Results: Total 107 radiomic features were extracted from pre-segmented liver metastases on patients’ Computed Tomography images. Among them, original shape sphericity, original glcm correlation, original gldm DependenceEntropy, and original glrlm RunEntropy were statistically significant for the prediction of OS, with a hazard ratio of -2.16 (CI 0.01-0.92; p value 0.04), 1.54 (CI 1.5-14.0; p value 0.006), 0.51 (CI 1.0-2.5; p value 0.02), and 0.52 (CI 1.0-2.6; p value 0.03), respectively. Conclusions: Our data analysis indicates crucial radiomic features that hold promise for predicting the clinical outcome of patients with colorectal cancer who have liver metastases. Future research with a larger sample size is warranted for the external validation of our results.
Efficacy of fadraciclib (CYC065), a novel dual CDK2/9 inhibitor, on patient-derived models of colorectal cancer.
Authors: Mohammad Zokaasadi, Erdem Altunel, Divya Lakshmi Dayanidhi, John B Mantyh, Wylie K Watlington, Shannon J. McCall, David Blake, Jason A. Somarelli, David S. Hsu
Journal: Journal of Clinical Oncology (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&amp;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 IC 50 values lower than chemotherapy or palbociclib (2.65±3.92µM for fadraciclib (CYC065) vs. 29.92±41.98µM for chemotherapy (P&lt;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&lt;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.
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: Ying Yuan, Ning Zhu, Xuefeng Fang, Chenhan Zhong, Dan Li, Liu-Hong Wang, Jun Li, Shanshan Weng, Hanguang Hu, Caixia Dong, Yongmao Song, Dong Xu, Jianwei Wang, LIfeng Sun, Jian Wang, Xiujun Liao, Ningjuan Yu, Suzhan Zhang, Ke-Feng Ding
Journal: Journal of Clinical Oncology (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]