Bolus 5-fluorouracil Research Articles

A randomized phase 3 trial of total neoadjuvant therapy (induction chemotherapy, neoadjuvant chemoradiation, neoadjuvant chemotherapy, and surgery) vs. standard long-term chemoradiation therapy (neoadjuvant chemoradiation, surgery, and adjuvant chemotherapy) in locally advanced rectal cancer

PurposeThe management of rectal adenocarcinoma has evolved during the last decade, shifting from a conventional neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy in all cases to a total neoadjuvant approach, especially in locally advanced tumors when a sphincter-sparing surgery has been planned. However, the exact indications and the neoadjuvant regimen with the highest response remain unresolved. We aimed to assess whether administering neoadjuvant chemotherapy before and after preoperative chemoradiotherapy could increase the pathological complete response (pCR) rates.MethodsWe conducted a phase 3, multicenter, randomized trial at four hospitals in Iran. Adult patients with a newly diagnosed, biopsy-proven, locally advanced non-metastatic rectal adenocarcinoma with an ECOG performance status of 0–2 were randomly assigned (2:2) to either the total neoadjuvant treatment (TNT) or the standard-of-care groups using a block randomized design. Investigators and participants were not masked to treatment allocation and groups. The TNT group received neoadjuvant chemotherapy with FOLFOX6 (intravenous 85 mg/m2 oxaliplatin and 400 mg/m2 leucovorin, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2,400 mg/m2 over 46 h every 14 days for four cycles before and four cycles after chemoradiotherapy), chemoradiotherapy (50.4 Gy during 28 fractions and 800 mg/m2 concurrent oral capecitabine twice daily 5 days per week), and total mesorectal excision. The standard-of-care group received neoadjuvant chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (eight cycles). The primary endpoint was the pathological complete response. Safety analyses were conducted on treated patients.ResultsOverall, 25 and 27 patients were enrolled in the TNT and standard-of-care groups, respectively. Both groups were similar in terms of gender, age, and tumor differentiation. The tumors in the standard-of-care group were significantly located closer to the anal verge compared with those in the TNT group (9.4 ± 3.7 cm in TNT vs. 6.8 ± 4 cm in standard, p = 0.02). A pCR was reached in 48% (12/25) and 25.9% (7/27) of patients in the TNT and standard-of-care groups, respectively (p = 0.4). The R0 resection rates were identical between the two groups (92% vs. 88.9%, p = 0.3). Moreover, the toxicity rates were similar between the two groups.ConclusionOur results showed that TNT is a safe and feasible treatment approach in patients with rectal cancer and may improve the overall pCR rate compared with standard treatment.Clinical trial registrationhttps://irct.behdasht.gov.ir/trial/65666, identifier IRCT20220723055527N1.

Is it Time to Forget the 5-Fluorouracil Bolus?

Is it Time to Forget the 5-Fluorouracil Bolus?

A multicenter, prospective, phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to an anti-EGFR antibody: HGCSG1801.

Aflibercept (AFL) plus FOLFIRI prolongs overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a prospective open-label phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese patients with mCRC failing a prior oxaliplatin-based chemotherapy plus an anti-EGFR agent. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months. Forty three patients were enrolled between November 2019 and October 2022. The primary endpoint was met: 6-month PFS rate was 58.8% (90% confidence interval [CI], 45.7%-72.0%). Median PFS and OS were 7.3 months (95% CI, 5.5-11.0 months) and 18.8 months (95% CI, 12.9-26.6 months), respectively. The overall response rate was 20.9% (95% CI, 10.0-36.0%) and disease control rate was 88.4% (95% CI, 74.9-96.1%). The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%), and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. This study suggests that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese patients with mCRC who failed prior oxaliplatin-based chemotherapy plus an anti-EGFR agent.

Hepatic artery infusion chemotherapy combined with immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced hepatocellular carcinoma with portal vein tumor thrombus: A single center retrospective study.

e16176 Background: Hepatic artery infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs, a triplet regimen) has shown promising results in advanced hepatocellular carcinoma (HCC); however, the real world outcomes for pts with portal vein tumor thrombosis (PVTT) need further clarification. This study aimed to investigate the effectiveness of the triplet regimen in HCC pts with PVTT. Methods: We retrospectively included pts who received HAIC plus anti-PD-1 antibodies, bevacizumab or lenvatinib as first-line therapy for HCC pts with PVTT between Apr 2021 and Dec 2022. Pts received HAIC of mFOLFOX (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; 5-fluorouracil bolus, 400 mg/m2 on day 1; 5-fluorouracil infusion, 2400 mg/m2 for 46 h). The combination of TKIs and ICIs included 6 patterns: tislelizumab and lenvatinib (TIS-LEN), sintilimab and lenvatinib (SIN-LEN), pembrolizumab and lenvatinib (PEM-LEM), camrelizumab and lenvatinib (CAM-LEN), sintilimab and bevacizumab (SIN-BEV), and atezolizumab and bevacizumab (ATE-BEV). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Results: A total of 113 pts were included, with a median age of 55 years (range 48-60). Pts characteristics were as follows: male (90.3%), hepatitis B (81.4%), BCLC C stage (100%), Child-Pugh A (92.9%), tumor number [ = 1 (45.1%), = 2 (10.6%), ≥3 (44.3%)], tumor diameter>10 cm (43.4%), extrahepatic metastasis (19.5%), beyond up to steven status (88.5%). Specific treatment options are as follows: HAIC-TIS-LEN (n = 57), HAIC-SIN-LEN (n = 21), HAIC-PEM-LEM (n = 6), HAIC-CAM-LEN (n = 12), HAIC-SIN-BEV (n = 14), and HAIC-ATE-BEV (n = 3). As of Dec 31, 2023, the median follow-up duration was 18.4 mo (95% CI, 16.7-25.1), and the median number of HAIC was 2.5 (range 2-3). The median PFS was 8.1 months (95% CI, 6.8-9.8), while the median OS reached 17.7 months (95% CI:14.5-27.6). ORR was 51.3% (3 CR, 55PR), DCR was 91.2% per RECIST 1.1; ORR was 64.6% (18 CR, 55 PR), DCR was 92% per mRECIST. 15 pts (13.3%) received surgical treatment after conversion, 13 of whom remains tumor-free to date. Among those who develop disease progression, 35.3% pts (29/83) underwent a subsequent regimen that included TACE. The most common TRAEs were hypoalbuminemia (41.6%), abdominal pain (36.3%), anorexia (33.6%), hypertension (27.4%) and hypothyroidism (25.6%). The most common grade 3-4 TRAEs included hypertension (10.6%), leukocytes count decreased (9.7%), abdominal pain (8.8%), proteinuria (6.2%) and hypoalbuminemia (5.3%). Conclusions: This study further demonstrates the clinical benefit of HAIC plus ICIs and TKIs for HCC pts with PVTT. In the future, prospective studies are warranted.

A real-world experience of hepatic arterial infusion chemotherapy combined with tislelizumab and lenvatinib for unresectable hepatocellular carcinoma with type IV portal vein tumor thrombus.

e16154 Background: Clinical improvement of interventional therapy with PD-(L)1 inhibitors plus molecular targeted therapies in have been confirmed by several studies, such as EMERALD-1, CHANCE001 etc. Limited data of this treatment in unresectable hepatocellular carcinoma (uHCC) patients (pts) with type IV portal vein tumor thrombus (PVTT) is available. This study aims to describe the efficacy and safety in uHCC pts with type IV PVTT (Vp4) who received HAIC combined with tislelizumab and lenvatinib (HAIC+Tisle+Len) in the real-world setting. Methods: This was a single-center, retrospective analysis of Vp4 uHCC pts treated with HAIC+Tisle+Len as first line systemic therapy between Apr 2020 and Dec 2022. Patient characteristics, treatment information, adverse events and survival data were collected. Pts received HAIC of modified FOLFOX (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; 5-fluorouracil bolus, 400 mg/m2 on day 1; 5-fluorouracil infusion, 2400 mg/m2 for 46 h), lenvatinib (8 or 12 mg once daily for body weight, 60 or ≥60 kg), and tislelizumab (200 mg q3w). HAIC was allowed to repeat on demands. Outcomes evaluated included overall survival (OS), progression free survival (PFS), overall response rate (ORR), overall disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: A cohort of 54 pts was identified with a median age of 55 years (range 49-59). Pts characteristics were as follows: male (90.7%), hepatitis B (79.6%), BCLC C stage (100%), Child-Pugh A (88.9%), tumor number [ = 1 (50%), = 2 (7.4%), ≥3 (42.6%)], tumor diameter ≥10 cm (42.6%), extrahepatic metastasis (7.4%), beyond up to steven status (90.7%). As of Dec 20, 2023, the median follow-up duration was 21.3 mo (95% CI, 16.1-26.0), and the median number of HAIC was 3 (range 2-4). The median PFS was 8.1 months (95% CI, 6.8-12.3), while the median OS reached 16.8 months (95% CI:13.1-NR). ORR was 53.7% (3 CR, 26 PR) per RECIST 1.1; ORR was 66.7% (12 CR, 24 PR) per mRECIST. DCR was 96.3% per either RECIST 1.1 or mRECIST. Two pts received surgical treatment after conversion, one of whom underwent liver transplantation and remains tumor-free. The post-PD therapies after first-line treatment were as follows: Tisle+Len (24.1%), TACE+Tisle+Len (18.5%), Tisle+Len+Radiotherapy (7.4%), HAIC+Tisle+Regorafenib (5.6%), others (18.5%). The most common grade 3-4 TRAEs were hypertension (14.8%), decrease in albumin (11.1%), anorexia (9.3%), leukopenia (9.3%), abdominal pain (7.4%) and AST/ALT elevation (7.4%). Conclusions: The combination of HAIC with tislelizumab and lenvatinib represents a promising efficacy and manageable safety for uHCC pts with Vp4, which supplements the trial data for Vp4-HCC with real world outcomes.

TACE-HAIC combined with donafenib and immunotherapy for hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT): A retrospective analysis.

e16174 Background: The probability of Chinese hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) is relatively large and the long-term survival of this part of patients is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. We want to explore the efficacy and safety of TACE plus hepatic arterial infusion chemotherapy combined with Donafenib, anti-PD-1 antibody in uHCC patients with PVTT. Methods: We retrospectively analyzed the patients who were diagnosed as uHCC with PVTT and received the treatment of TACE plus HAIC combined with Donafenib, anti-PD-1 antibody as first-line therapy from Dec 2021 to Jun 2023 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS) and safety. Results: Of 106 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m2 2h, leucovorin 400 mg/m2 1h, fluorouracil bolus 400 mg/m2 in the first 10 minutes, and fluorouracil infusion 2400 mg/m2 for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (IQR, 52-64). The study population was predominantly male (79.2%), and 79.2% were HBV-positive. All HCC patients are accompanied by PVTT, most of which are VP3(72.6%).The rate of patients with extrahepatic metastasis were 16.0%. All patients were classified as BCLC stage C and 84.0% were classified as CNLC stage IIIa. As of December 2023, 106 patients had received at least one imaging evaluation, 11 (10.4%), 60 (56.6%) and 28 (26.4%) of them achieved complete response, partial response and stable disease, and the overall objective response rate and disease control rate was 67.0% and 93.4% per modified RECIST criteria respectively. With 16.3 months of median follow-up time, the 12-month PFS rate was 81.3% and the 12-month OS rate was 90.1%. The median PFS and OS were not reached. 103 of all patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 33 (31.1%) patients, and no grades 4 or 5 were reported. The most common Grade 3 TRAEs included aspartate transaminase increased (18.9%), platelet count decreased (14.2%) and blood bilirubin increased (8.5%). Conclusions: TACE-HAIC combined with Donafenib and immunotherapy are effective and tolerable for uHCC patients with PVTT.

Apatinib and camrelizumab plus hepatic arterial infusion with oxaliplatin and 5-fluorouracil vs. apatinib and camrelizumab as the first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A randomized multi-center clinical trial.

TPS4194 Background: The combination of immune checkpoint inhibitors and antiangiogenic drugs has been approved as the first-line treatment for advanced hepatocellular carcinoma (HCC). However, the survival benefit is still limited, especially in patients with high-risk features (Vp4, and/or bile duct invasion and/or tumor occupancy of ≥50% of the liver). Hepatic arterial infusion chemotherapy (HAIC) plus apatinib (an antiangiogenic drug) and camrelizumab (a PD-1 antibody) showed encouraging antitumor activity for these patients in a previous phase 2 study. Herein, we investigated the efficacy and safety of apatinib and camrelizumab plus HAIC compared with apatinib and camrelizumab as the first-line treatment for HCC with portal vein tumor thrombus (PVTT). Methods: In this randomized, open-label, phase 3 trial, eligible patients are ≥18 years with HCC confirmed by radiology, histology, or cytology. Other eligibility criteria were as follows: with PVTT, ECOG PS 0/1, no history of systemic therapy, not amenable to curative treatment approach, Child-Pugh A class liver score, and ≥1 measurable lesion by RECIST v1.1. A total of 214 patients (anticipated) will be randomized (1:1) to receive apatinib (250mg orally once daily) and camrelizumab (200 mg IV Q2W) plus HAIC with FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 20 hours via hepatic artery Q4W) or apatinib (250mg orally once daily) and camrelizumab (200 mg IV Q2W) until disease progression or intolerable toxicity. Stratification will be by patients with or without high-risk features. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, objective response rate per RECIST 1.1 and mRECIST, disease control rate per RECIST 1.1 and mRECIST, time to progression, duration of response, time to response, and safety. Whole-Exome Sequencing and RNA Sequencing of tumor biopsy samples were performed for predictive biomarker exploration. Clinical trial information: NCT05198609 .

Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and tislelizumab for unresectable hepatocellular carcinoma: A single-arm, phase II study.

500 Background: Unresectable hepatocellular carcinoma (uHCC) patients (pts) had high unmet medical needs in practice. Retrospective studies suggested a potent antitumor effect and long-term survival benefit of hepatic arterial infusion chemotherapy (HAIC) plus programmed death-1 inhibitor and lenvatinib. This prospective phase II study aimed to evaluate the efficacy and safety of HAIC combined with lenvatinib and tislelizumab in uHCC pts. Methods: Eligible pts were aged ≥18 years and had histologically confirmed uHCC, ECOG PS ≤1, Child-Pugh (C-P) A/B, and ≥1 measurable lesion per RECIST 1.1. Pts received HAIC of modified FOLFOX (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; 5-fluorouracil bolus, 400 mg/m2 on day 1; 5-fluorouracil infusion, 2400 mg/m2 for 46 h), lenvatinib (8 or 12 mg once daily for body weight <60 or ≥60 kg), and tislelizumab (200 mg every 3 weeks). HAIC was allowed to repeat on demands. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included ORR per mRECIST, disease control rate (DCR), surgical conversion rate, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Between June 2021 and January 2023, 46 pts were enrolled. The median age of pts was 51-year-old, most were male 42 (91.3%), ECOG PS 0 33 (71.7%), C-P A 44 (95.7%), tumor diameter ≥10 cm 31 (67.4%), multiple tumors 33 (71.7%), vascular invasion 38 (82.6%), extrahepatic metastasis 7 (15.2%). As of August 15, 2023, . All pts entered efficacy and safety analysis, ORR was 52.2% (0 complete response [CR], 24 partial response [PR]) per RECIST 1.1; ORR was 84.8% per mRECIST, with 5 CR and 34 PR. DCR was 95.6% per either RECIST 1.1 or mRECIST. Surgical conversion rate was 21.7% (10/46). Median PFS was 10.9 (95% CI, 8.0-13.8) months; 12-month OS rate was 41.3%. COX analysis revealed that ECOG PS 1 (HR, 3.17; 95% CI, 1.43-7.03; p=0.005), multiple tumors (HR, 3.68; 95% CI, 1.22-11.14; p=0.021), and extrahepatic metastasis (HR, 4.04; 95% CI, 1.57-10.40; p=0.004) were independently associated with poor PFS. Any-grade AEs occurred in 43 (93.5%) pts, the most common were proteinuria (43.4%), aspartate aminotransferase (AST) increased (35.8%), and alanine aminotransferase (ALT) increased (32.1%). Grades ≥3 AEs occurred in 10 (21.7%) pts and mainly included AST increased (7.5%), hypertension (3.8%), and hyperbilirubinemia (3.8%). Conclusions: HAIC combined with lenvatinib and tislelizumab showed meaningful clinical benefits and acceptable safety in uHCC pts. The study is ongoing, OS will be reported later. Clinical trial information: ChiCTR2200064384 .

First-line FOLFOX therapy for advanced esophageal squamous cell carcinoma: Multicenter prospective study in Japan.

280 Background: Cisplatin (CDDP) plus fluoropyrimidine was the standard first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). FOLFOX is promising option especially in patients with ESCC intolerant to CDDP but there were limited data on efficacy and safety of FOLFOX. We conducted a multicenter prospective observational study of FOLFOX for Japanese patients with ESCC intolerant to CDDP. Methods: Eligible participants had clinical stage IVB ESCC, with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, intolerant to CDDP, but tolerant to FOLFOX. FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 2400 mg/m²) was administered every 14 days. The primary endpoint was the response rate (RR) by RECIST v1.1 and the null hypothesis of RR was 10%. Based on the assumption of performing a one-sided test with an α of 0.10, 29 patients were needed to ensure the statistical power of 90% assuming RR of 30%. Results: In this study, 31 patients were enrolled from 14 hospitals between Apr. 2021, and Jul. 2022 and 30 patients received FOLFOX. The patient characteristics were: median age, 77 (range 66–89); male/female, 30/1; ECOG PS 0/1/2, 16/12/3; median creatinine clearance, 49.9 ml/min (33.4–80.2); median G8 score, 12 (range 7–17); and median CARG score, 8 (range 6–13). As the data cutoff of Jul 2023, all 30 patients discontinued FOLFOX. The reason for treatment discontinuation was disease progression, 86.7%; adverse events, 13.3%. Median follow-up time (interquartile range: IQR) was 20.2 (IQR 13.7–23.1) months. Median number of cycles administered were 5 (range 1–24). The RR was 22.6% (80%CI 0.13–0.35; p = 0.031) and disease control rate was 42.0%. Median progression-free survival was 3.9 months (95% CI 2.3–6.1). Median overall survival was 13.3 months (95% CI 9.5–not reached). The incidence of grade 3 or higher adverse events was 40% (neutropenia 26.7%, anemia 3.3%, nausea 6.7%, anorexia 6.7%, infection 6.7%, peripheral sensory neuropathy 3.3%). There was no treatment related death. Twenty-three patients (76.7%) received subsequent therapies, such as nivolumab (70%). Conclusions: First-line FOLFOX showed an acceptable safety profile and the prespecified statistical efficacy target was achieved. FOLFOX might be a treatment option for advanced ESCC patients who are intolerant to CDDP. Clinical trial information: UMIN000044485 .

Anlotinib combined with penpulimab and hepatic artery infusion chemotherapy (HAIC) in the first-line treatment of unresectable hepatocellular carcinoma.

TPS579 Background: Hepatic arterial infusion chemotherapy (HAIC) is recommended as a treatment option in patients with advanced hepatocellular carcinoma (HCC). Anlotinib plus penpulimab, a humanized anti-PD-1 IgG1 antibody, has shown encouraging activity in the treatment of advanced HCC in an open-label phase II trial (NCT 04172571). Considering different anti-malignancy mechanisms, combining systemic and locoregional therapies may show a potential synergic effect and promising preliminary efficacy results in advanced HCC. Consequently, the aim of this study is to assess the efficacy and safety of Anlotinib, Penpulimab, plus HAIC for advanced HCC. Methods: Trial design: This single-arm, prospective, phase II study will include treatment-naive adult (≥18 years) patients with advanced HCC, ECOG PS 0-2, and Child-Pugh class A-B. A total number of 26 patients will be enrolled for treatment until disease progression or intolerable toxicity. Patients will receive anlotinib(10 mg, p.o., qd, d1-14, q3w), penpulimab (200 mg, i.v., d1, q3w) and HAIC (d1- d2) with the FOLFOX regimen (oxaliplatin 85-130 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 hours) for 4-6 cycles, followed by maintenance therapy with anlotinib and penpulimab for up to 2 years. The primary endpoint is objective response rate (ORR)), evaluated using RECIST 1.1. Secondary endpoints are median PFS and overall survival (OS), disease control rate (DCR) per RECIST 1.1, quality of life (QOL) and safety. Recruitment for this study will complete in December 2024.

A O03 Host phenotypic adversity independently predicts progression to resection in neoadjuvantly-treated pancreatic cancer

Abstract Background Neoadjuvant treatment (NAT) offers a modest survival benefit to the otherwise dismal outcomes of pancreatic ductal adenocarcinoma (PDAC), however methods for assessing treatment response and disease trajectory during NAT are limited. Cachexia and sarcopenia are hallmark features of PDAC and defining host phenotypic adversity is crucial in understanding the tumour-host relationship and its influence on clinical outcomes. We sought to determine the relationship between body composition, systemic inflammation, and outcomes in NAT PDAC to lay foundations for improving assessment of treatment response. Methods This is a retrospective, observational study with an intention-to-treat design, analysing resected (n = 109) and non-resected (n = 117) NAT PDAC (total n = 226) from the tertiary West of Scotland Pancreatic Unit, Glasgow Royal Infirmary. Patients were included if they had resectable or borderline resectable disease and received NAT. Patients were excluded if they had locally advanced or metastatic disease. Body composition was determined by single-slice L3 cross-sectional measurements. Results Patients with an adverse phenotype defined by change in body composition were less likely to progress to resection (40.9% vs 68.8%, p < 0.001). Logistic regression confirms the independence of this effect (OR 3.79, 95% CI 1.99-7.22, p < 0.001). There was a trend towards systemic inflammation in the non-resected group (CRP rise 51.4% vs 29.9%, p = 0.008). Patients treated with Folfirinox who required dose reduction received higher doses of irinotecan, 5-fluorouracil (bolus) and 5-fluorouracil (infusion) per unit muscle mass (7.3 vs 6.9mg/cm2⋅m-2, p = 0.010; 16.2 vs 14.7mg/cm2⋅m-2, p = 0.002; 96.5 vs 91.1mg/cm2⋅m-2, p = 0.026). Conclusions Host phenotypic adversity during NAT presents a potentially valuable addition to a limited arsenal of tools to aid decision making in resectable and borderline resectable PDAC. Early assessment of body composition trend during chemotherapy may present an opportunity to switch the host phenotype from adverse to favourable in some patients, or highlight the futility of continuing aggressive treatment in others. Chemotherapeutic prescribing by body surface area overlooks crucial differences in lean body mass and may be exposing patients to avoidable and burdensome toxicities.

Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study

BackgroundHepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC. MethodsThis retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 administered on day 1, and 5-fluorouracil 2400 mg/m2 infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m2 and raltitrexed 3 mg/m2 on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile. ResultsORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia. ConclusionThe effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) is often treated with a mFOLFOX6 regimen. The 5-fluorouracil (5-FU) bolus is often omitted from the regimen to reduce the risk of hematological adverse events (AEs) in patients with poor performance status. We aimed to investigate the incidence of hematological AEs in Asian patients with mCRC who were treated with the mFOLFOX6 with and without 5-FU bolus dosing. This retrospective chart review was conducted at King Chulalongkorn Memorial Hospital, Thailand from June 2021 to June 2022. The primary endpoints were hematological AEs. Secondary endpoints were any AEs. The comparison of continuous data was conducted with an independent t-test. The Chi-squared test was used to compare categorical data. From 110 patients, we found that hematological and non-hematological AEs of any grade in the two groups were not significantly different. However, patients in the bolus arm had a significantly lower absolute neutrophil count (ANC) than those in the non-bolus arm (mean difference = 43.13 (95% confidence interval (CI): 20.74, 65.51), P-value = 0.0002). A subgroup analysis in patients who received first-line treatment with mFOLFOX6 showed that the bolus arm had a significantly lower ANC (mean difference = 46.01 (95% CI: 19.99, 72.03), P-value = 0.0007). mCRC patients who were treated with bolus 5-FU had lower ANC. The 5-FU bolus omission from the mFOLFOX6 regimen may be required in patients with a high risk of neutropenia.

First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group

Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. Roche and Amgen.

Real-world treatment patterns and total cost of care in Medicare patients with metastatic pancreatic ductal adenocarcinoma who received first-line FOLFIRINOX.

e16283 Background: Modifications to the FOLFIRINOX (FFX) regimen are used in the real world to attempt to decrease side effects and increase tolerability for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). This study assesses patterns in real-world modifications to first-line (1L) FFX and total cost of care per administration cycle in the Medicare Fee-For-Service (FFS) population. Methods: We used ICD-10 diagnosis codes to identify patients aged 65+ with mPDAC without end-stage renal disease in the 2018-2021 Medicare Parts A, B, and D 100% Research Identifiable Files (RIF) data. Study patients had 2+ claims with a pancreatic cancer diagnosis and at least one diagnosis of a metastasis anytime on or after the first pancreatic cancer diagnosis. Total cost of care (TCOC) represents mean Medicare paid amounts and patient cost sharing. Lines of therapy (LOTs) were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. Study patients were assigned to cohorts based on drugs present within a 48-hour (2-day) period of a 1L FFX chemo infusion cycle: FFX with all 4 component drugs (oxaliplatin, irinotecan, leucovorin, 5-Fluorouracil (5-FU) bolus and infusion), FFX with no 5-FU bolus but with 5-FU infusion, FFX with a 5-FU bolus but no 5-FU infusion, FFX with no 5-FU of any kind, and FFX with no leucovorin. Results: We found 45,755 administrations of 1L FFX regimens across 8,889 patients with mPDAC between 2018 and 2021. Among 1L FFX regimens, the largest cohort was comprised of administrations involving a 5-FU infusion but no 5-FU bolus (21,619 administrations, or 47%). The second largest cohort received all 4 FFX component drugs (15,565 administrations, or 34%). The other cohorts were patients receiving FFX with no leucovorin (6,300 administrations, or 14%), FFX with a 5-FU bolus but no infusion (1,425 administrations, or 3%) and patients receiving FFX with no 5-FU of any kind (842 administrations, or 2%). Administrations containing all 4 drug components had the highest cost per cycle ($7,515), and those with no 5-FU of any kind had the lowest ($6,715). Conclusions: Among Medicare beneficiaries receiving 1L FOLFIRINOX (FFX) regimens to treat mPDAC, only 34% of administrations of FFX contained all four components. Administrations most frequently omitted the 5-FU bolus. Administrations containing all 4 drug components had higher costs per cycle and those with no 5-FU of any kind had the lowest cost per cycle.

Alternating short-course oxaliplatin-based chemotherapy and nivolumab as first-line treatment of patients with abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC): A randomized phase 2 trial.

3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplatin-based therapy and if followed by ICB (without concomitant chemotherapy that might compromise an invoked tumor-defeating immunity) may result in durable clinical response for patients with abdominal metastases. Methods: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable, ECOG performance status 0-1, and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to FLOX (oxaliplatin 85 mg/m2 day 1, bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg days 1-2) Q2W (control arm) or alternating cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W (experimental (exp) arm) with break periods at prespecified intervals. Response assessment per i/RECIST by blinded central review was done every 8 weeks with progression-free survival (PFS) as primary endpoint. Sample size of 40 in each arm with 1:1 randomization would detect exp arm doubling of median PFS. Associations between PFS and relevant patient and disease variables were estimated by Cox proportional-hazards regression models. Prespecified correlative analyses included circulating tumor DNA (ctDNA) by droplet digital PCR and circulating immune cell composition by high-dimensional single-cell mass cytometry. Results: Of 80 enrolled subjects (05/2018-10/2021), 76 intention-to-treat (ITT) cases were equally allocated to the study arms and followed to censoring at 10/2022 with identical median PFS of 9.3 months (95% CI, 6.4-12.9 (control arm) and 4.6-15.2 (exp arm)). The adjusted Cox model revealed interaction between age and study arm, as patients ≥60 years had significantly lowered risk of progression when receiving exp therapy (median PFS 13.6 months (95% CI, 8.5-18.8); p = 0.022). No unexpected adverse events were recorded; specifically, no grade ≥4 immune-mediated adverse event occurred. Of note, 17% of exp arm patients had durable complete response, among whom all BRAF-mutant cases ( n = 3) with PFS 21-35 months and rapid clearance of baseline BRAF-mutant ctDNA (control arm BRAF-mutant cases ( n = 10), median PFS 3.6 months). Responding exp arm patients showed distinct subsets of circulating immune cells with more homogenous profiles than ICB-unresponsive subjects. Conclusions: With equal primary endpoint for the ITT cases, alternating short-course oxaliplatin-based therapy and nivolumab significantly improved PFS compared to standard first-line chemotherapy in MSS-CRC patients ≥60 years with abdominal metastases. Clinical trial information: NCT03388190 .

Donafenib, anti-PD-1 antibodies, plus hepatic arterial infusion chemotherapy (HAIC) as conversion therapy in patients with initially unresectable hepatocellular carcinoma (HCC): A prospective, single-arm, phase 2 study.

e16140 Background: Most patients with hepatocellular carcinomas (HCC) are diagnosed at intermediate to advanced stages, at which they have missed the opportunity for curative resection. Combination therapy with tyrosine kinase inhibitors, anti-PD-1 antibodies and HAIC has achieved a high response rate for advanced HCC. Phase 3 study also showed the survival benefit of donafenib for unresectable HCC compared with sorafenib. This study aimed to explore the efficacy and safety of conversion therapy with HAIC plus donafenib, anti-PD-1 antibodies in the patients with initially unresectable HCC. Methods: This was a prospective single-arm, phase 2 study (ChiCTR2200059297). Eligible patients were adults who were newly diagnosed with HCC, not amenable to curative resection, with an ECOG PS 0-1 and Child-Pugh class A/B7. Patients received FOLFOX HAIC (oxaliplatin 85 mg/m2 3h, leucovorin 200 mg/m2 2h, fluorouracil bolus 400 mg/m2 in the first 15 minutes, and fluorouracil infusion 2400 mg/m2 for 46 hours) Q3W plus donafenib 200mg bid, anti-PD-1 antibodies Q3W until disease progression or unacceptable toxicity, followed by multidisciplinary assessment and potential hepatectomy. The primary endpoint was conversion success rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), pathologic complete remission (pCR), event free survival (EFS), overall survival (OS) and safety. Results: From Sep 2021 to Dec 2022, 22 pts were enrolled with a median age of 57 years (range, 43-76). The study population was predominantly HBV-positive (71.4%). All pts were in BCLC stage C, the rate of macro vascular invasion and retroperitoneal lymph node metastasis were 71.4% and 28.6% respectively. As of Jan 31, 2023 cut-off, 19 pts were evaluable for response. The conversion success rate was 52.6% (10/19) and 4 pts received hepatectomy. Among the 4 pts, 1 (25%) case achieved complete pathological response and 2 (50%) cases achieved major pathological response. Based on mRECIST, ORR was 84.2% (95%CI, 0.60-0.90) with 2 (10.5%) complete responses (CR) and 14 (73.7%) partial responses (PR). DCR was 94.7% (95%CI, 0.74-0.99). The 12 months’ EFS rate was 50.4%, the median EFS and OS were not reached. All pts were evaluable for toxicity, and 18 (81.8%) pts had at least one treatment-emergent AE (TEAE). TEAEs occurring in ≥20% of pts were decreased platelet count (36.4%), hand-foot skin reactions (31.82%), rash (27.3%), elevated ALT (22.7%) and decreased WBC count (22.7%). 10 (45.5%) pts had level 3 TEAE. There were no level 4 and 5 TEAEs. Conclusions: A triple combination of donafenib, anti-PD-1 antibodies and HAIC is well tolerated and effective, it’s a feasible conversion therapy for patients with unresectable locally intermediate to advanced HCC. The enrollment and follow-up are continuing. Clinical trial information: ChiCTR2200059297 .

Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody for unresectable hepatocellular carcinoma (uHCC): A retrospective analysis.

e16163 Background: Chemoembolization plus hepatic arterial infusion chemotherapy significantly improved ORR and PFS over chemoembolization alone in patients with uHCC in previous study. And donafenib showed the survival benefit and better safety compared with sorafenib in a Phase III trial. In consideration of synergism, we evaluated the safety and efficacy of TACE plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody in patients with uHCC. Methods: We retrospectively analyzed the patients who were diagnosed as unresectable hepatocellular carcinoma and received the treatment of TACE plus HAIC combined with donafenib, anti-PD-1 antibody as first-line therapy from Nov 2021 to Nov 2022 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS), time to response (TTR) and safety. Results: Of 36 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m2 2h, leucovorin 400 mg/m2 1h, fluorouracil bolus 400 mg/m2 in the first 10 minutes, and fluorouracil infusion 2400 mg/m2 for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (range, 44-80). The study population was predominantly male (75%), and 89% were HBV-positive. Patients were classified as BCLC stage A (8.3%), stage B (8.3%) and stage C (83.4%). The rates of patients with portal vein tumor thrombus and extrahepatic metastasis were 69% and 11% respectively. 30.6% patients received interventional therapy before the combination treatment. By Feb 2023, 23 patients had received at least one imaging evaluation, 19(82.6%) of them achieved partial response, ORR and DCR were 82.6% and 100% per modified RECIST criteria respectively. And the median TTR was 1.1 months. With 3.8 months of median follow-up time, the 6-month PFS rate was 51.2%. The median PFS and OS were not reached. All 36 patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 8 (22.2%) patients, and no grades 4 or 5 were reported. The most common TRAEs included alanine aminotransferase increased (77.8%), alkaline phosphatase increased (77.8%), platelet count decreased (69.4%) and blood bilirubin increased (63.9%). Conclusions: Chemoembolization plus hepatic arterial infusion chemotherapy combined with donafenib, anti-PD-1 antibody are effective and tolerable for uHCC patients.

Donafenib combined with hepatic artery infusion chemotherapy (HAIC) and sintilimab for unresectable hepatocellular carcinoma (uHCC): A prospective, single-arm phase II trial (DoHAICs study).

e16165 Background: The combination of anti-angiogenesis and immune checkpoint inhibitors has been proved to improve clinical outcomes of uHCC, but efficacy still does not meet clinical needs. In Phase III study (ZGDH3), donafenib showed the survival benefit and better safety compared with sorafenib. HAIC significantly improved treatment responses over TACE in patients with large uHCC in a Phase III trial. Considering the different mechanisms, this study aimed to investigate the safety and efficacy of HAIC combined with donafenib and sintilimab in patients with uHCC. Methods: This is a prospective, single-arm phase II study (NCT05166772). Patients with histologically diagnosed uHCC, no previous systemic treatment, Child-Pugh A5-B7, ECOG performance status (PS) of 0 or 1 were eligible for inclusion. Enrolled patients received donafenib (200 mg, bid), sintilimab (200 mg, q3w) and HAIC (oxaliplatin 85 mg/m2 2h, leucovorin 400 mg/m2 2h, fluorouracil bolus 400 mg/m2 in the first 10 minutes, and fluorouracil infusion 1200 mg/m2 for 23 hours, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Results: From December 2021 to December 2022, 24 patients (19 men and 5 women; median age, 58 years) were enrolled: BCLC stage A/B/C: 2/9/13; Child-Pugh class A/B: 23/1; ECOG PS 0/1: 23/1. There were 19 (79.2%) pts with hepatitis B. The median tumor size was 7.9 cm (range, 1.7-16.3), 45.8% pts presented macro vascular invasion, the invasion rates of Vp3, Vp4 and inferior vena cava were 25.0%, 4.2% and 8.3% respectively, 16.7% had extrahepatic metastasis. As of February 10, 2023, the median follow-up time was 107 days, the median number of HAIC was 3 times (range, 1-8). Based on mRECIST, the ORR was 78.3% (95% CI, 56.3%-92.5%) with 3 (13.0%) complete responses (CR) and 15 (65.2%) partial responses (PR). The disease control rate (DCR) was 95.7% (95% CI, 78.1%-99.9%). Of 23 pts evaluable for response, the conversion success rate was 65.2% (15/23), 10 of them (43.5%) received hepatectomy, 3 cases (30.0%) achieved complete pathological response and 5 cases (50.0%) achieved major pathological response. The median time to response (TTR) was 1.9 months (range, 1.2-5.2). The median progression-free survival (PFS) was 10.2 months (95% CI, NR) and 6 months PFS rate was 89.1%. The median duration of response (DoR) was not reached. Any grade treatment-emergent adverse events (TEAEs) occurred in 95.8% of pts. The most common TEAEs were thrombocytopenia (66.7%), neutropenia (45.8%), rash (41.7%). Grade 3-4 TEAEs occurred in 37.5% of pts. No grade 5 TEAEs were observed. Conclusions: Preliminary analysis showed that donafenib combined with HAIC and sintilimab showed promising clinical benefits and acceptable toxic effects in patients with uHCC. The enrollment and follow-up are continuing. Clinical trial information: NCT05166772 .

Hepatic arterial infusion chemotherapy (HAIC) combined with tislelizumab and lenvatinib for advanced hepatocellular carcinoma (aHCC) with Vp3-4 portal vein tumor thrombosis (PVTT): A single-arm, phase II study.

e16145 Background: aHCC patients (pts) with Vp3-4 PVTT have a poor prognosis. HAIC combined with immune checkpoint inhibitors and targeted therapies has shown local control and survival benefits in aHCC. However, the optimal combination in aHCC pts with Vp3-4 PVTT remains unclear. Here, we reported the preliminary efficacy and safety of HAIC combined with tislelizumab and lenvatinib in this population. Methods: In this ongoing, single-site, prospective, single-arm, phase II study, eligible pts were aged ≥18 years, histologically confirmed aHCC, ECOG PS ≤1, Child-Pugh A/B, and had at least 1 measurable lesion per RECIST 1.1. Pts received HAIC with modified FOLFOX (oxaliplatin, 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1; and 5-fluorouracil infusion 2400 mg/m2 for 46 h), combined with lenvatinib (8 or 12 mg QD for body weight &lt;60 or ≥60 kg) and tislelizumab (200mg Q3W). HAIC was conducted repeatedly on demand. The primary endpoint was the objective response rate (ORR) per RECIST 1.1. Secondary endpoints included the ORR per mRECIST, disease control rate (DCR), surgical conversion rate, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: From June 2021 to January 2023, 27 aHCC pts with Vp3-4 PVTT were enrolled; of these, 22 pts were valuable for efficacy and safety analyses. The 22 pts were characterized with a median age of 52.5 years (range 33-72), 40.9% ECOG PS 0, 90.9%Child-Pugh A, and 45.5% extrahepatic metastasis. Till data cut-off (January 20, 2023), median follow-up was 11.3 months (95% CI, 6.0-13.1), 17 pts were alive and 14 pts remained on treatment. The ORR was 45.5% (95% CI, 25.1%-67.3%) with all partial responses per RECIST 1.1. Notably, 17 of 22 pts (77.3%; 95% CI, 54.2%-91.3%) achieved objective response as per mRECIST, with 6 (27.3%) complete responses and 11 (50%) partial responses. The DCR was 90.9% (95% CI, 69.4%-98.4%) either by RECIST 1.1 or mRECIST. Surgical conversion was achieved in 22.7% (5/22; 95% CI, 8.7%-45.8%) pts. Median PFS was not reached, with a 6- and 12-month PFS rate of 50% and 27.3%. OS data was not mature by the cut-off date. TRAEs were reported in 18 of 22 pts (81.8%). Most common TRAEs of any grade were hypertension (11/22, 50%), neutropenia (10/22, 45.5%), and aspartate aminotransferase (AST) increased (7/22, 31.8%). Grades ≥3 TRAEs occurred in 6 pts (27.3%), including 3 neutropenia (13.6%), 2 abdominal pain (9.1%), and 1 AST increased (4.6%). Conclusions: HAIC combined with tislelizumab and lenvatinib showed encouraging clinical activity and acceptable toxicity in aHCC pts with Vp3-4 PVTT, suggesting that this combination could be considered in this population. Study enrollment is ongoing, more mature data will be presented later. Clinical trial information: ChiCTR2200064384 .