Common Treatment-related Adverse Events Research Articles

A phase I/Ib study of the aurora kinase A inhibitor alisertib in combination with osimertinib in advanced osimertinib-resistant EGFR-mutated lung cancer.

8572 Background: The third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutated lung adenocarcinoma (LUAD), however treatment resistance invariably occurs. We previously identified Aurora Kinase A (AURKA) activation as a mechanism of resistance to osimertinib. Alisertib is an oral, selective, small-molecule inhibitor of AURKA. We evaluated the combination of alisertib with osimertinib in a phase I/Ib study of patients with advanced EGFR-mutated LUAD who experienced disease progression on prior treatment with osimertinib monotherapy. Methods: 21 total patients were treated in an open-label, single-center phase I trial (NCT04085315). 10 patients were treated in a 3+3 dose escalation phase with alisertib using an intermittent dosing strategy of 30 mg (n = 6) or 40 mg (n = 4) twice daily (BID) on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily. 11 additional patients were treated at the 30 mg alisertib intermittent dosing schedule in combination with osimertinib 80 mg daily in a Phase Ib dose expansion. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of the alisertib and osimertinib combination. Secondary endpoints were investigator-assessed objective response rate (ORR) by RECIST 1.1 criteria, depth of response (DoR), disease control rate (DCR) for at least 12 weeks, progression-free survival (PFS) and overall survival (OS). Results: 21 patients with stage IV EGFR-mutated LUAD (76.1% exon 19 deletion; 14.3% L858R; 9.5 % L861Q) who had progressed on osimertinib were enrolled. 10 (47.6%) patients had received only first-line osimertinib, while 11 (52.3%) had received ≥ 2 lines of prior therapy. Common treatment-related adverse events were neutropenia (42.9%), anemia (42.9%), and diarrhea (38.1%). 2 patients had dose limiting toxicities from grade 4 neutropenia at the alisertib 40mg BID dose level. 2 patients had serious adverse events related to the study drugs, including grade 3 constipation and grade 4 anemia. There were no treatment-related deaths. Intermittent alisertib 30 mg BID with osimertinib 80 mg daily was the MTD and R2PD. ORR for all enrolled patients was 9.5% (95% CI: 1.2% to 30.4%), DCR was 81% (95% CI: 58.1% to 94.6%), and median DoR was -4 % (95% CI: -15% to 10%). The median PFS was 5.5 months (95% CI: 3.7 – 13.2 months) and median OS was 23.5 months (95% CI: 11.9 months – NR). Conclusions: Intermittent dosing of alisertib 30 mg BID in combination with osimertinib 80 mg daily demonstrated no dose limiting toxicities and was identified as the RP2D. While ORR was < 10%, DCR was > 80% and the median PFS was 5.5 months. These results are comparable to other emerging therapies for patients with advanced osimertinib resistant EGFR-mutated LUAD and warrants further exploration. Clinical trial information: NCT04085315 .

A single-arm exploratory clinical study of β-glucan combined with camrelizumab and SOX chemotherapy as first-line treatment for advanced gastric adenocarcinoma.

e16008 Background:The combination of immunotherapy plus chemotherapy has revolutionized the therapy pattern of advanced gastric adenocarcinoma, but the efficacy is still unsatisfactory. β-glucan has been reported to be a potential natural immune modulator for tumor growth inhibition. Therefore, we aimed to evalute the efficacy and safety of β-glucan plus immunotherapy and chemotherapy in the first-line treatment of advanced gastric adenocarcinoma. Methods:This is a prospective, single-arm, investigator-initiated trail. All included patients are adults with advanced gastric adenocarcinoma, and with an Eastern Cooperative Oncology Group (ECOG) score ≤ 2. Eligible patients received WGP β-glucan (500 mg; twice daily on days 1-14) + camrelizumab (day 2; fixed-dose 200 mg) + oxaliplatin (day 1; 130 mg/m2)+ oral S-1 (twice daily on days 1-14; body surface area < 1.25 m2: 40 mg; body surface area 1.25-1.5 m2: 50 mg; body surface area > 1.5 m2: 60 mg) every 3 weeks. The curative effect is evaluated (RECIST 1.1) every 2 cycles. Safety evaluation indicators include vital signs, laboratory indicators and treatment-related adverse events (TRAEs). The primary endpoints were objective response rate (ORR) and safety; the secondary endpoints were median progression-free survival (mPFS) and median overall survival (mOS); the exploratory endpoint treatment-related biomarker changes from liquid biopsies. Results:From April 2021 to October 2022, a total of 30 patients with average of 67.5 years old had been enrolled, incuding 20 (66.7%) males and 8 (26.7%) patients with an ECOG PS score of 2. The ORR was 60%; the mPFS was 10.4 months (95% confidence interval [CI], 9.52-11.27); the mOS was 14.0 months (95% CI, 11.09-16.91). A total of 19 patients (63.3%) had TRAEs, with 9 patients (30%) with grade ≥ 3. The most common treatment-related adverse events were nausea (53.3%) and hemangioma (33.3%). No TRAEs associated with β-glucan were observed. After 2 cycles of treatment, the levels of IL-2 and IFN-γ significantly increased ( P < 0.05), and the number of CD4+ T cells also significantly increased ( P < 0.05). Furthermore, the protein expressions of GZMA, GZMH, and CD244 were significantly lower in the responding group (CR+ PR) than in the non-responding group (SD + PD) (P < 0.05). Conclusions: This preliminary study demonstrates that β-glucan plus camrelizumab and SOX chemotherapy offers favorable efficacy and a manageable safety profile in patients with advanced gastric adenocarcinoma, and further studies are needed to verify its efficacy and safety. Clinical trial information: ChiCTR2100044088.

The safety and short-term efficacy of selective internal radiation therapy combined with systemic treatment for unresectable malignant hepatic tumors in Chinese patients.

e16247 Background: There are many systemic treatment options for patients with unresectable malignant hepatic tumors. In China, selective internal radiation therapy (SIRT) with yttrium-90 (Y90) resin microspheres was approved until 2022. The aim of this retrospective study was to investigate the safety and short-term efficacy of SIRT with Y90 resin microspheres followed by systemic treatment in Chinese patients. Methods: The study analyzed patients who received SIRT with Y90 combined with systemic treatment at our center between June 2022 and October 2023. The study's primary endpoint was to determine the objective response rate (ORR), while safety was the secondary endpoint. Response was measured based on modified Response Evaluation Criteria in Solid Tumors criteria (mRECIST) up to 90 days after the initial therapy. Safety was evaluated using the Common Terminology Criteria for Adverse Events Version 5.0. Results: 21 patients wereincluded, of whom 22 times of SIRT were performed. 18 patients had HCC, and 3 had mCRC.The baseline characteristics of the patients are shown in Table. The median age was 54 years (IQR, 48-59 years) and 90.5% of patients were male. According to Eastern Cooperative Oncology Group performance status, grade 0 and grade 1 were 81% and 19%, respectively, whereas Child-Pugh A represented 90.5% of cases. The proportion of patients with hepatitis B virus infection was 95.2%. Thirteen (61.9%) patients received different treatments before SIRT. The median number of tumors was 2.5 (IQR, 1-4.3), whereas the median diameter of the largest lesion was 100.4 mm (IQR, 68.3-127.7 mm). PVTT was classified as follows: Vp1 (n = 3), Vp2 (n = 2), Vp3 (n = 2) and Vp4 (n = 1). Median AFP was 33.2 ng/mL (IQR, 5.9-401 ng/mL). The median total radiation activity administered was 1.4 GBq (IQR, 0.9-2.7 GBq) and the median target tissue dose was 205 Gy (IQR, 155-242 Gy). Nine (43%) patients were downstaged to surgery. Four (19%) patients had a complete response, fifteen (71.4%) had a partial response and two (9.5%) had a progressive disease. ORR and disease control rate were 90.5% and 90.5%, respectively. None of the patients experienced grade 3 and higher adverse events. The most common treatment-related adverse events were fever and abdominal pain, which required no special treatment. Conclusions: SIRT with Y90 resin microspheres combined with systemic treatment is safe and effective in patients with unresectable malignant hepatic tumors, which resulted in encouraging ORR (90.5%) and a downstaging rate (43%). Clinical trial information: ChiCTR2300077524. [Table: see text]

Clinical outcomes from a phase I clinical trial of a novel oncolytic virus VG161 in patients with hepatocellular carcinoma (HCC) refractory after 2 prior lines of therapy including checkpoint inhibitors (CPI).

4105 Background: This study aims to investigate the safety and anti-tumor activity of VG161 expressing IL12, IL15/IL15 receptor α unit, and PD-L1 blocking peptide in patients with HCC refractory to standard therapies. Methods: The study was conducted as a multicenter phase I trial with fast titration and 3+3 dose escalation part (A) and expansion part (B), which enrolled patients with primary liver cancer refractory to standard therapies. Patients in part A were dosed in 5 cohorts on days 1, 2 and 3 by image-guided intratumoral injections with dosing ranges from 1.0×10^8 to 5×10^8 PFU per 28 days treatment cycles. Part B used a single arm Simon's two-stage design at the recommended phase 2 dose (RP2D). The study endpoints were safety, and efficacy assessed by objective response rate (ORR) and Disease Control Rate (DCR) by RECIST1.1 and mRECIST (HCC), PFS and OS. Pretreatment HCC tumor samples were collected and analyzed by RNAseq. Results: 44 patients including 40 HCC (Male/Female: 37/3; median age: 58years) were dosed and no DLTs were reported. The most common Treatment-Related Adverse Events (TRAEs) was fever, which was resolved with symptomatic treatment. RP2D was determined as 1ⅹ10^8 PFU daily on day 1, 2 and 3 of each cycle. Of 40 HCC patients, 35 failed after 2 prior lines of therapy and were eligible for tumor assessment. ORR was 17.14% (6/35), DCR was 60.00% (21/35). The median PFS and OS were 2.90 (95%CI: 1.85-3.95) and 9.40 (95%CI: 0.47-18.33) months respectively. Statistically significant OS prolongation was observed in a subgroup of 22 HCC patients who progressed after receiving at least 3 months of CPI (PreCPI>3 m) as compared to those who received CPI for ≤3 months (PreCPI ≤ 3 m). The median OS was 17.30 months (95%CI: 5.35-29.25) vs. 7.40 months (95%CI: 5.11-9.69), HR: 0.32 (95%CI: 0.10 to 0.98) (p<0.05). Patients who received targeted or CPI therapies after VG161 survived longer than those who did not receive any anticancer treatment although they all previously failed such therapies [20.10 months (95%CI: 13.19-27.01) vs. 8.80 months (95%CI: 6.34-11.26), HR: 0.30 (95%CI: 0.10-0.88), P<0.05]. PreCPI>3 m and anti-cancer treatment after VG161 were the 2 independent factors with significant impact on OS (P<0.05). A gene signature was identified based on RNAseq data which predicted the prolonged OS in the study patients (P<0.01) but not in patients retrieved from TCGA database. Conclusions: VG161 was well tolerated and demonstrated comparable ORR and DCR with other CPIs data in 2L HCC. VG161 also prolonged survival in a subgroup of patients identified by prior treatment or gene signature, supporting further studies with enrichment of patients who may benefit from the treatment. The implications of pre/post VG161 CPI treatment on OS underscore a combination strategy for improving outcomes. Clinical trial information: NCT04806464 .

Tislelizumab with anlotinib and chemotherapy for second-line treatment of pancreatic ductal adenocarcinoma: A pilot study early result.

e16316 Background: Advanced pancreatic ductal adenocarcinoma is a malignant tumor with poor prognosis. At present, chemotherapy is still the standard treatment, however the efficacy is unsatisfied. The lack of second-line treatment options for pancreatic cancer results in progression-free survival often lasting less than 3 months. For pancreatic cancer is an immune desert type of tumor, immunotherapy has not brought breakthrough therapeutic regimen compared to the remarkable data in other tumors.There is still insufficient therapeutic evidence treated with PD1 antibody in pancreatic cancer. Anlotinib is a tyrosine kinase inhibitor (TKI) with anti-tumor effects. It has been shown the combination of PD1 and multi-target tyrosine kinase inhibitors can increase immunotherapy efficacy. The purpose of this study is to evaluate the efficacy and tolerability of Tislelizumab combined with Anlotinib, as well as chemotherapy (the choice of the investigator) in second-line treatment of patients with pancreatic ductal adenocarcinoma. Methods: In this single arm, phase II, prospective exploratory study, it was planned to recruit 30 adult patients with treated pancreatic ductal adenocarcinoma who have never received any PD (L) 1 and TKI. Eligible patients received Tislelizumab (iv, 200mg, Q3W), Anlotinib (PO, 10mg, QD), and chemotherapy (determined by the researchers) till disease progression or death. The primary endpoint was median progression-free survival (mPFS), the secondary endpoints were objective response rate (ORR), median overall survival(mOS), disease control rate (DCR), and treatment safety profile. Results: 14 eligible patients were recruited till Jan 2024, 12 patients with PFS records were included. Median follow-up time was 208 days (104 days-504 days). mPFS was 106 days, OS is not reached, BOR (best of response) was stable disease. The 3-months DCR rate was 58.3%, 6-months DCR rate was 25%. One patient was observed to have a 20% tumor shrinkage after two cycles of treatment and is still being followed up. The most common treatment-related adverse events(TRAEs) was neutropenia with level ≤grade 3, observed in 8/14 patients. The immune-related adverse event of concern was hypothyroidism(grade 1/2), which occurred in two patients. Two patients experienced grade 4 obstructive jaundice caused by the progression of the disease. Conclusions: The second-line combination regimen of Tislelizumab with Anlotinib based on chemotherapy demonstrated survival improvement trend and no new safety signals identified in pancreatic cancer. These data suggest Tislelizumab + Anlotinib+Chemo may be a promising novel treatment option for patients with pancreatic cancer. Clinical trial information: NCT05681390 .

Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle invasive bladder cancer (MIBC) with HER2 expression.

4568 Background: Disitamab vedotin (DV) is a novel humanized anti-HER2 antibody-drug conjugate. DV plus toripalimab (a recombinant humanized anti-PD-1 monoclonal antibody) showed promising antitumor activity in metastatic urothelial carcinoma (ASCO 2023). This study aimed to evaluate the safety and efficacy of DV plus toripalimab as neoadjuvant therapy in MIBC patients with HER2 expression. Methods: This is a prospective multicenter phase 2 trial which planned to enroll 40 pts. Primary endpoint is pathological CR (pCR) rate; secondary endpoints include pathologic response rate, safety and tolerability. Study enrolled pts who are previously untreated MIBC (cT2-T4aN0-1M0), medically fit for and agree to undergo curative intent RC+PLND. HER2 expression was required to be immunochemistry (IHC) ≥ 1+ tested locally. Pts received DV 2 mg/kg plus toripalimab 3 mg/kg every two weeks for 6 cycles, followed by RC+ PLND within 4 weeks. Here we present preliminary efficacy and safety results. Results: 44 pts were enrolled and clinical stage at diagnosis was: cT2N0 (38.6%), cT3N0 (29.5%), cT4aN0 (13.6%), cT2-4aN1 (18.2%). HER2 expression of IHC 1+, 2+ or 3+ was 11.4%, 56.8%, and 31.8%, respectively. By the data cut-off date (Feb-2024), 29 pts (65.9%) completed RC + PLND. The pCR rate was 62.1% (18/29). The pathologic response rate was 75.9% (22/29). Common treatment-related adverse events (TRAEs) were mostly Grade 1 or 2, including alopecia (36.4%), alanine aminotransferase increased (31.8%), aspartate aminotransferase increased (25.0%), rash (22.7%), gamma-glutamyl transferase increased (22.7%), peripheral sensory neuropathy (22.7%), and asthenia (20.5%). Grade 3-4 TRAEs were reported in 15.9% of pts. No deaths occurred. No surgery was cancelled due to TRAEs. Survival data are not yet mature. Conclusions: Neoadjuvant treatment with DV plus toripalimab showed promising efficacy results and was well tolerated in operable MIBC pts with HER2 expression. These results will support further investigation for DV plus toripalimab in this population. Clinical trial information: NCT05297552 .

Postoperative adjuvant hepatic arterial infusion chemotherapy combined with donafenib in hepatocellular carcinoma with solitary large tumor and microvascular invasion: A multicenter, prospective, single-arm, phase II trial.

e16227 Background: Hepatocellular carcinoma (HCC) with solitary large tumor (≥ 5 cm) and microvascular invasion (MVI) was associated with high 5-year recurrence rate and poor survival prognosis. Postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) was found to improve the recurrence-free survival (RFS) with acceptable safety profiles in HCC patients with MVI. However, the prognosis of HCC who received adjuvant HAIC after hepatectomy still remain far from satisfactory. Several studies have shown that the combination of HAIC and tyrosine kinase inhibitors (TKIs) could exhibit a synergistic anticancer effect and improve the survival outcomes of advanced HCC. Thus, the present study was conducted to explore the efficacy and safety of adjuvant HAIC plus the novel multikinase inhibitor donafenib in HCC with solitary tumor ≥ 5 cm and MVI. Methods: This prospective, single-arm phase II study was conducted in three medical centers in China. HCC patients with both solitary tumor ≥ 5 cm and MVI, no evidence of recurrence at radiological follow-up at 4-8 weeks after hepatectomy, no previous treatment for HCC other than hepatectomy, Child-Pugh score A or B7 were enrolled. Eligible patients received one cycle of HAIC with oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX4), and followed by donafenib (200 mg orally twice daily) for up to 1 year until disease recurrence or unacceptable toxicity. The primary endpoint was 1-year recurrence-free survival rate (1-year RFS rate). Secondary endpoints included RFS, overall survival (OS) and safety. Results: A total of 18 patients were included for analysis. The median age was 59 years (range, 28–75), the median maximum tumor size was 7.0 cm (interquartile range [IQR], 6.2–7.8), 88.9% had low-risk MVI, 61.1% had Edmondson-Steiner grade III-IV and 44.4% had incomplete tumour capsule. As of November 27, 2023, 4 of 18 patients (22.2%) recurrenced and no deaths occurred with a median follow-up of 15.0 months (95% confidence interval [CI], 5.1–19.1). The 1-year RFS rate was 64.9% (95%CI, 39.2%–100%), and current immature median RFS was 14.3 months (95%CI, not available [NA], 11.2–NA). The most common treatment-related adverse events (TRAEs) were hand-foot skin reaction (72.2%), diarrhea (38.9%), decreased platelet count (22.2%), hypoalbuminemia (22.2%), and alopecia (22.2%). Grade 3 TRAEs occurred in 6 patients (33.3%), and no grade 4 or 5 TRAEs occurred. Conclusions: In this prospective study, the preliminary data indicated that HAIC combined with donafenib is an encouraging adjuvant therapy with well-tolerated safety profiles for HCC patients with solitary tumor ≥ 5 cm and MVI. Clinical trial information: NCT04962958 .

Neoadjuvant serplulimab in combination with concurrent chemoradiotherapy for locally advanced, resectable esophagogastric junction adenocarcinoma.

e16103 Background: Surgery combined with perioperative therapy was recommended as standard treatment for patients with locally advanced esophagogastric junction (EGJ) adenocarcinoma, but the survival rate was still poor. Immunotherapy has shown antitumor activity and an acceptable safety profile in advanced EGJ cancer. The aim of this study was to evaluate the efficacy and safety of neoadjuvant Serplulimab combined with concurrent chemoradiotherapy in previously untreated locally advanced resectable EGJ adenocarcinoma. Methods: Eligible patients with resectable EGJ(Siewert Type II and Type III, Siewert classification 2000)adenocarcinoma stage cT3-4 or N+ were enrolled. Patients received neoadjuvant Serplulimab (300mg on day 1) plus SOX(oxaliplatin at 130mg/㎡on day 1; TS1 40-60mg two times per day on D1-D14, Q3W) in first cycle, followed by Serplulimab (300mg on day 1) combined with concurrent chemoradiotherapy (Reduced SOX regimen: oxaliplatin at 100mg/㎡on day 1, TS1 40-60mg two times per day on D1-D14, Q3W; Radiotherapy dose:45Gy in 25f) in second and third cycle. The patient finished the preoperative treatment and rested for 6-8 weeks for surgery. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints were major pathological response(MPR) rate, R0 resection rate, objective response rate(ORR), disease-free survival(DFS), overall survival(OS), and toxicity. Results: From March 8, 2023 to January 31,2024,15 patients were enrolled. Nine patients completed neoadjuvant therapy. Eight of these patients underwent radical surgical resection. One out of nine achieved a confirmed pathological complete response (pCR) after three cycles of neoadjuvant treatment. Additionally, two out of nine patients achieved major pathological response(MPR). So, the pCR rate was 11.1%, and the MPR rate was 22.2%. The Tumor and Lymph Nodes downstaging rates are 62.5% and 87.5%, respectively. The median DFS and OS were not reached. In terms of safety, fifteen patients who received at least one cycle of neoadjuvant therapy were included. The most common treatment-related adverse events(TRAE) across all grades were nausea/vomiting(6/15), anorexia(5/15), thrombocytopenia(4/15), and fatigue(4/15). Four patients (26.7%) had grade≥3 adverse events during preoperative therapy, with thrombocytopenia(3/15) and hepatic veno-occlusive disease(1/15). Immune-related adverse reactions(irAE) included myositis(1/15) and rash(1/15), both were grade 1. No grade 4 or higher TRAEs were observed. Conclusions: Initial benefits were demonstrated when using Serplulimab with concurrent chemoradiotherapy for the treatment of locally advanced, resectable EGJ adenocarcinoma patients. The efficacy and safety of Serplulimab with chemoradiotherapy will be further investigated in this trial later. Clinical trial information: NCT05918419 .

Phase I/II first-in-human study to evaluate the safety and efficacy of tissue factor-ADC MRG004A in patients with solid tumors.

3002 Background: Tissue factor (TF) overexpression is associated with thrombosis, metastasis and poor prognosis in solid tumors, including cervical and pancreatic cancer. MRG004A is a novel anti-TF monoclonal antibody conjugated (ADC) to MMAE payload (drug-to-antibody ratio: 3.8), utilizing Glycoconnect site-specific conjugation technology. Herein, we present the preliminary safety and efficacy data from phase I/II MRG004A-001. Methods: This is an interim report (Data cutoff: Dec 15, 2023) of first-in-human, dose-escalation and expansion study ongoing in the USA and China. Pts with ECOG 0-1 with unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy, received MRG004A monotherapy Q3W intravenously. The primary objectives were to assess the safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Baseline tissue was evaluated for the association of TF expression with objective response rate (ORR) and disease control rate (DCR). Results: Sixty-three pts were enrolled with 43 in dose-escalation phase (8 dose levels [0.3-2.6mg/kg]) and 20 in dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). Median age 58 (38-75). ECOG0: 8 (13%) pts. Female: 37 (59%) pts. Median 3 prior lines of therapy: 3 (1-10). MTD was not reached. Sixteen baseline samples were evaluated for overall % membrane positivity by immunohistochemistry. Nineteen were pancreatic cancer (PC) and 68% (13/19) had TF ≥50% and 2 or 3 (+). Five received dose <2 mg/kg Q3W. Significant anti-tumor activity of MRG004A was observed in pts with PC. Among 12 evaluable pts with PC in the 2.0mg/kg cohort, who have received median 3 lines of prior therapy, there were 4 PR and 6 SD. ORR was 33.3% (4/12) and DCR was 83.3% (10/12). Among them, 5 pts with PC of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2mg/kg. 4 of 5 TF-overexpressed PC achieved PR and 1 SD. Also, MRG004A showed efficacy in other cancers. In 4 pts with heavily-treated triple-negative breast cancer (TNBC), ORR and DCR were 25% (1/4) and 50% (2/4), respectively. In 2 pts with cervical cancer with four prior therapy lines, 1 PR and 1 SD. Common treatment-related adverse events (TRAE) of any grade include conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%) and 7.9% (5/63) pts had serious adverse events. One pt with TNBC treated at 1.8mg/kg experienced G3 Steven Johnson Syndrome, a dose-limiting toxicity (DLT), but resolved. No other DLT was observed and dose expansion and matured outcome evaluation is ongoing. Conclusions: MRG004A demonstrated a manageable toxicity and a striking antitumor activity across multiple tumor types with high TF expression in heavily pretreated setting, including pancreatic cancers. These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors. Clinical trial information: NCT03941574 .

Efficacy and safety of disitamab vedotin (RC48) in HER2-expressing breast cancer: A multicenter retrospective study.

e13011 Background: RC48 is an Antibody-Drug Conjugate (ADC) that integrates a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) linked to the microtubule inhibitor monomethyl auristatin E (MMAE). This study reports real-world data using RC48 monotherapy in HER2-expressing advanced breast cancer (ABC). Methods: The study reviewed patients with HER2-expressing ABC who received RC48 monotherapy at three hospitals in China between September 2021 and June 2022. The electronic medical record was used to collect the clinical characteristics of the patient and to evaluate the antitumor activity and safety. The primary outcome was real-world progression-free survival (rwPFS). Results: A total of 15 patients were included, of whom 9(60%) were HER2-positive and 6(40%) had HER2 low expression (IHC 1+ or IHC 2+/ISH-).11 patients (73.3%) had visceral metastases, 40% of patients (6/15) had central nervous system (CNS) metastases at baseline. 6 patients (40%) had ≥3 metastatic lesions, and 13(86.7%) of patients received RC48 as third-line treatment or higher. Progression-free survival (PFS), overall survival (OS), and response can be assessed in all patients. The median follow-up was 10 months and the median rwPFS was 8.0 months (95% CI, 4.897-11.103), while the median OS was not reached. Objective response rate (ORR) and disease control rate (DCR) were 46.7% and 80% respectively. Partial response (PR) was achieved in 46.7% of the patients (7/15). patients with HER2-positive and HER2 low expression, the median rwPFS was 8.77 and 4.63 months, respectively (HR = 0.49,95% Cl, 0.13-1.80, P = 0.196), and in 6 patients with CNS metastases, the median rwPFS was 7.5 months (95% CI, 2.82-18.28). The most common treatment-related adverse events (TRAEs) were elevated transaminase (33.3%) and Leukopenia (33.3%), most of which were grade 1-2, No serious adverse events related to treatment were observed. Conclusions: The novel HER2-targeted ADC, RC48, demonstrated promising preliminary antitumor activity in patients with HER2-expressing ABC, patient with brain metastases could also benefit, with tolerable toxicities.

Durvalumab plus gemcitabine/cisplatin/nab-paclitaxel in resectable biliary tract cancer: A phase II, single-arm, open-label study (DurGAP).

e16260 Background: Biliary tract cancer (BTC) presents a formidable challenge, marked by its aggressive nature and dismal prognosis. While surgical resection remains the lone potentially curative option, 5-year survival rates have plateaued below 50%, largely due to high rates of recurrences and metastases. Given these sobering statistics, the imperative for neoadjuvant therapy to enhance outcomes is evident. Building upon the success of the TOPAZ-1 trial, which established durvalumab in combination with gemcitabine and cisplatin as a standard regimen for advanced BTC, this study seeks to assess the safety and efficacy of incorporating neoadjuvant durvalumab alongside gemcitabine, cisplatin, and Nab-paclitaxel for resectable BTC. Methods: Resectable, treatment-naïve BTC patients (pts) were enrolled and administered 3 cycles of neoadjuvant durvalumab (1000mg, iv, d1, q3w) + GAP (gemcitabine 1000mg/m2, cisplatin 25mg/m2, Nab-paclitaxel 100mg/m2, d1, d8, 21d cycle). Primary endpoints included assessing Adverse Events (AEs) and Objective Response Rate (ORR). Secondary endpoints comprised R0 resection rate, Recurrence-Free Survival (RFS), Overall Survival (OS). Results: Between Feb, 2023 to Jan, 2024, a total of 24 patients were enrolled, 12 (50.0%) were male, all with ECOG 0 and 18 (75.0%) presenting with N1 status. Median age: 65 years. Primary sites: intrahepatic (50.0%), extrahepatic (33.3%), gallbladder (16.7%). Median follow-up: 8.75 months; all pts received ≥2 neoadjuvant cycles. The ORR was 62.5%, with all 15 pts demonstrating partial responses (PR). The DCR was 87.5% with 15 PR and 6 stable disease (SD) responses. The most common treatment-related adverse events (TRAEs) were increased ALT/AST (28.6%), anemia (21.8%), hypoalbuminemia (16.0%). Grade ≥3 TRAEs occurred in 2 (8.3%) pts. 13 pts underwent resection, achieving R0 resection in 12 (92.3%) of cases, comprising 10 PR, 2 SD, and 1 pt deemed eligible for surgery post-assessment despite a PD response. 11 pts did not undergo resection, with reasons including patient refusal (4 PR, 1 SD), not meeting resection criteria (2 PD), lost to follow-up (1 PR, 1 SD), and still under active follow-up (2 SD). Conclusions: Neoadjuvant durvalumab combined with gemcitabine/cisplatin/Nab-paclitaxel demonstrated a promising ORR and DCR, with a tolerable safety profile, warranting further investigations in a larger cohort. Clinical trial information: NCT05640791 .

Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2−) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2− mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446.

Utidelone for heavily pretreated metastatic castration-resistant prostate cancer after failing docetaxel treatment: An open-label, single-arm, phase II trial.

e17036 Background: The appropriate chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel treatment remains unmet medical needs. Utidelone (UTD1) is a genetically engineered epothilone analog with antitumor activity in taxane-resistant cancers. UTD1 was approved for advanced breast cancer in 2021. This study was designed to evaluate the safety and efficacy of UTD1 in mCRPC. Methods: In this perspective, phase II clinical trial, men with progressive mCRPC after docetaxel and abiraterone, and/or enzalutamide, and/or apalutamide received UTD1 monotherapy treatment at a total dose of 150 mg/m2 for five days intravenous, every three weeks until disease progression, or intolerable toxicity, or death. We reported the preliminary results for potential benefits in this new treatment. The primary endpoint was prostate specific antigen (PSA) response rate, defined as a 50% or greater reduction in serum PSA. The secondary endpoint included investigators-assessed objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1, radiographic progression-free survival (rPFS) according to PCWG3 criteria, overall survival (OS), and safety. The trial was registered at Chinese Clinical Trial Registry (No. ChiCTR2200061635). Results: By January 31st, 2024, twenty-five mCRPC patients with a median age of 67 years were enrolled in this study at Sun Yat-sen University Cancer Center since March 23rd, 2022. Patients received an average of 4.2 lines of prior anticancer treatments: 100% of them received docetaxel, 96.0% of them received abiraterone, and 80.0% progressed after enzalutamide, and/or apalutamide. 28.0% of patients had visceral metastases, and 88.0% patients had bone metastases. At of the cut-off date, the PSA response rate was 16.0%. The median rPFS and OS were 4.9 months and 7.1 months, respectively. One patient had a durable response for 19.2 months and had been remaining on study treatment to date. One PR and four SD were observed in ten patients with measurable lesions, resulting in an overall ORR and DCR of 10.0% and 50.0%, respectively. The most common treatment-related adverse events (TRAEs) including peripheral sensory neuropathy (76.0%), dyspepsia (72.0%), anemia (64.0%), constipation (60.0%), fatigue (64.0%), nausea (36.0%), leukocytopenia (32.0%), arthralgia (32.0%), dizziness (32.0%), vomiting (20.0%), and diarrhea (20.0%) were manageable. The 3/4 grade TRAEs included anemia (16.0%), and diarrhea (4%). No treatment-related death occurred. Conclusions: UTD1 has demonstrated promising efficacy and favorable tolerance in heavily pretreated mCRPC patients after progression on docetaxel in the preliminary analyses. Additional randomized trials are warranted for this new regimen. Clinical trial information: ChiCTR2200061635.

Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial.

e16158 Background: PD-1 or PD-L1 inhibitors plus chemotherapy as the first-line treatment has been proven to be effective in improving the prognosis of advanced biliary tract cancer (BTC) patients. However, there is still considerable demand for further improvement of BTC patients’ prognosis. This trial aims to evaluate the efficacy and safety of Cadonilimab (PD-1/CTLA-4, a bi-specific antibody) plus gemcitabine and cisplatin for patients with advanced BTC in first -line treatment. Methods: In this phase II, single-arm trial, we will enroll 65 patients with previously untreated, unresectable, locally advanced or metastatic BTC, including intrahepatic or extrahepatic cholangiocarcinoma (ICC/ECC) and gallbladder carcinoma (GBC). Participants received Cadonilimab (10 mg/kg, days 1, every three weeks) plus gemcitabine (1000 mg/m2, days 1, 8, Q3W), and cisplatin (25 mg/m2, days 1, 8, Q3W) for up to eight cycles, followed by Cadonilimab (10 mg/kg, days 1, Q3W) until disease progression or unacceptable toxicity. Treatment response was evaluated with image-based assessment according to response evaluation criteria insolid tumors (RECIST) version 1.1. by two experienced experts and further explored multiple methods, such as 3D visualisation and Spectral computed tomography Scan. The primary endpoint was the objective response rate (ORR); the secondary endpoints are disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included associations between response, molecular characteristics, and the immune microenvironment. Results: Between June 30, and January 31, 2024, a total of 30 patients have undergone at least one imaging evaluation. 66.7% of these patients were diagnosed with ICC, 23.3% with GBC, and 10% with ECC. The mean age was 58.4 years, and 60% of the patients were male. 24 (80%) patients had metastasis. Among them, 1 (3.3%) patient acheived complete response (CR), 15 (50%) patients had partial response (PR) and 8 (26.7%) patients presented with stable disease (SD). The ORR was 53.3% and the DCR was 80%. The most common treatment-related adverse events (TRAEs) of any grade were rash (80%) and anaemia (76.7%). Grade 3 TRAEs were observed in 66.7% of the patients. The most frequent grade 3 TRAEs were anaemia (33.3%), and leukocytopenia (33.3%). No grade 4 or 5 events were observed. All patients were microsatellite stable (MSS), and the median TMB was 2.88 (0-109.44) Muts/Mb. Conclusions: Cadonilimab plus gemcitabine and cisplatin shown a promising efficacy and acceptable safety profile as first-line treatment for advanced BTC patients. Clinical trial information: NCT05978609 .

A phase I clinical trial investigating the safety, tolerability, and pharmacokinetics of HX301 (narazaciclib), a novel multi-kinase inhibitor targeting CSF1R, CDK 4/6, and ARK5, in patients with advanced solid tumors.

e15106 Background: HX301 (narazaciclib) is a promising novel multi-kinase inhibitor with potent activity against Colony Stimulating Factor 1 Receptor (CSF1R), Cyclin-Dependent Kinase 4/6 (CDK4/6), and Aurora Kinase 5 (ARK5), with a half-maximal inhibitory concentration (IC50) values in 0.29-4.95 nM range. It is an oral bioavailable agent and has the ability to cross blood-brain barrier. Preclinical data have showed significant antitumor activities, warranting further clinical trials to evaluate the safety, and potential efficacy in human subjects. Methods: Utilizing the standard 3+3 design, the study aimed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of HX301. Patients with heavily pretreated advanced solid tumors received HX301single agent via oral administration, with doses ranging from 40mg to 200mg once daily for the first 21 days of each 28-day cycle. Results: As of December 27, 2023, a total of 20 patients (5 males, 15 females) were enrolled in the study, with varying doses of HX301 administered: 40 mg (n=3), 80 mg (n=3), 120 mg (n=4), 160 mg (n=3), and 200 mg (n=7). The median age of the patients was 55 years, ranging from 30 to 71. Notably, 15 patients (75%) had metastatic breast cancers. Dose-limiting toxicities (DLTs) were observed in 2 patients in the 200 mg group. These included a Grade 4 increase in alanine aminotransferase (ALT) and a Grade 3 decrease in platelet counts with associated epistaxis, both of which resolved after discontinuation of treatment. The most common treatment-related adverse events (AEs) observed were elevated aspartate aminotransferase (AST) (65.0%), decreased white blood cell count (50%), decreased neutrophil count (50%), elevated ALT (45%), elevated creatine kinase (45%), and elevated creatinine (35%). Additionally, 4 patients experienced Grade 3 or higher treatment-related AEs, including 1 patient in the 160 mg group with Grade 3 elevated γ-glutamyl transferase and alkaline phosphatase, and 3 patients in the 200 mg group with Grade 4 elevated ALT and Grade 3 elevated AST and Dyspepsia, Grade 3 decreased neutrophil and platelet counts, and Grade 3 hyperglycemia. Notably, no AEs led to death. Among the 20 patients evaluable for tumor assessment using RECIST 1.1 by Investigators, 4 obtained stable disease, including 2 patients in the 200 mg group, 1 in the 120 mg group, and 1 in the 80 mg group. Furthermore, 1 patient with HR+ breast cancer in the 200 mg group received study drug for over a year and achieved prolonged stable disease for more than 12 months, highlighting a notable clinical outcome. Conclusions: HX301 at dose levels ranging from 40mg to 160mg was tolerable with a manageable toxicity profile. Further clinical studies are needed to explore the drug's anti-tumor activity, particularly in combination settings. Clinical trial information: NCT05731934 .

Prognostic analysis of PD-1/CTLA-4 bispecific antibody combined with chemotherapy first-line treatment for recurrent or metastatic cervical cancer: A multicenter real-world study.

e17520 Background: PD-1/CTLA-4 bispecific antibody, cadonilimab, has shown excellent efficacy in advanced cervical cancer patients who have previously received platinum containing chemotherapy. However, its effectiveness in first-line treatment remains unclear yet. This study aims to evaluate the efficacy, safety, and prognostic biomarker of cadonilimab combined with chemotherapy for the first line treatment of recurrent or metastatic cervical cancer. Methods: Information on patients with recurrent or metastatic cervical cancer who received chemotherapy combined with cadonilimab as first-line treatment at three cancer centers from July 2022 to September 2023 were collected. Patients have not received systemic chemotherapy previously and are not suitable for curative local treatment, received cadonilimab 10mg/kg Q3W for up to 17 cycles + chemotherapy for up to 6 cycles (paclitaxel 135-175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bevacizumab 10-15 mg/kg. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. RNA-seq was used to analyze differential expressed genes (DEGs) between PR+CR group and PD+SD group. Results: There are 52 patients enrolled, median age 56.5 years (39–87 years). The median follow-up time was 12 months (5–23 months). There were 29 cases of lung metastasis, 7 cases of liver metastasis, 11 cases of bone metastasis, 12 cases of pelvic metastasis, and 11 cases of lymph node metastasis. The median number of cycles of cadonilimab and chemotherapy were 8 and 5, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 91% and 72.5%, respectively. The objective response rate (ORR) was 75%.The expression of PD-L1 and bevacizumab had no effect on prognosis. The most common treatment-related adverse events (TRAEs) were neutropenia (78.2%), anemia (82.7%), thrombocytopenia (51.9%), thyroid dysfunction (50%), nausea and vomiting (88.5%), fatigue (71.2%). Grade 3 or 4 adverse events (AE) were reported in 36.5% patients, mainly hematological toxicity. The most significant differential pathways between PR+CR group and PD+SD group were adhesion, Hippo signaling pathway, NOD like receptor signaling pathway, programmed cell death, and secretory granules. Conclusions: Cadonilimab combined with chemotherapy ± bevacizumab as first-line treatment for recurrent or metastatic cervical cancer was effective and well-tolerant.

Transarterial chemoembolization (TACE) combined with donafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A real-world clinical study.

e16145 Background: To evaluate the efficacy and safety of TACE combined with Donafenib, which is as a new tyrosine kinase inhibitors therapy recommended by the China liver cancer staging (CNLC) system for the treatment of unresectable hepatocellular carcinoma (uHCC). Methods: We conducted a single-center, retrospective study on patients diagnosed with uHCC treated by TACE plus Donafenib as the first-line therapy between May 2021 and September 2023 at The First Affiliated Hospital of Sun Yat-sen University. The primary outcomes evaluated in this study were progression-free survival (PFS) and overall survival (OS). Local response, one-year survival rate, safety and tolerability were the secondary outcomes. Results: All of 48 eligible patients by August, 2023, with the median age of 59 years. The clinical characteristics were as follows: BCLC stage A:2 (4.2%), B:16 (33.3%), and C:30 (62.5%); Child-Pugh class A:33 (68.8%) and B:15 (31.2%); ECOG PS 0: 27 (56.2%) and 1: 21 (43.7%). In this study, 10 (20.8%) patients had huge intrahepatic lesions, 15 (31.2%) subjects exhibited extrahepatic metastases at multiple sites, 19 (42.2%) patients presented with portal vein tumor thrombus, and 4 patients were diffuse-type HCC.107 TACE sessions were performed. Three patients had liver transplantation as frequent therapy, and histopathological examination of tissue from these subjects revealed complete necrotic foci. The median PFS was 12.8 months (95% CI: 8.66–NA) , mOS was not reached and the one-year OS rate was 87.5% (95% CI: 77%-97%) in the survival results. The tumor objective response rate was 58.3% with 14.5% complete response and 43.7% partial response based on mRECIST assessment. The disease control rate of the study group was 81.3%. The most common treatment-related adverse events (TRAEs) observed were elevated aspartate aminotransferase (AST) levels (75.0%), increase in bilirubin level (72.9%), elevated alanine aminotransferase (ALT) levels (54.2%), hand-foot syndrome (53.1%), diarrhea (29.1%), rashes (22.9%), hair loss (18.4%) and hypertension (12.5%). Twenty-three (46.9%) patients presented with grade 3 or 4 TRAEs including elevated AST levels (22.4%), elevated ALT levels (16.3%), increase in bilirubin level (4%), diarrhea (4%) and hypertension (2%). No Grade 5 TRAEs were observed. Conclusions: The combination of TACE and Donafenib presented good efficacy and tolerability, which could be potentially used as the first-line treatment of Chinese uHCC patients.

Stereotactic ablative radiotherapy combined with fruquintinib and tislelizumab in metastatic colorectal cancer: Updated findings from a single-arm, prospective phase II trial (RIFLE).

e15570 Background: Stereotactic ablative radiotherapy (SABR) has been shown to sensitize immunotherapy through inducing immunogenic death and remodeling the tumor immune microenvironment. In addition, anti-angiogenic therapy exhibits synergistic antitumor effects with PD-1/PD-L1 antibodies through its immunomodulatory effects for metastatic colorectal cancer (mCRC) patients. Here, we report the updated results from RIFLE trial: the efficacy and safety of the combination of fruquintinib, PD-1 inhibitor tislelizumab and SABR in mCRC patients. Methods: This is a single-center, single-arm, prospective phase II clinical trial (NCT04948034). mCRC patients with at least 2 measurable lesions (≥1 of which can be targeted with radiation and ≥1 lesion outside the radiation field) who have failed ≥ 1L standard therapy will receive SABR followed by fruquintinib (5 mg, d1-14, qd) and tislelizumab (200 mg, d1, q3w) within two weeks from completion of radiation. The percentage change from baseline in the sum of longest diameter of target lesions, consist of specified radiated and non-radiated lesions, will be assessed after at least 2 cycles’ drug treatment. Primary endpoint is best objective response rate (ORR) of target lesions. Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate and toxicity. Results: From August 2021 to February 2024, 34 patients were included in the trial and 31 in the efficacy analysis. Median age was 62 years, 24 (77.4%) patients were male, 26 (83.9%) had ≥ 3 metastases, and 14 (45.2%) had received ≥ 3 prior lines of systemic therapy. The biological effective dose (BED) for irradiated lesions ranged from 37.5 to 105 Gy. Median study follow-up was 17.3 months (95%CI:13.841-20.759), 24 patients were alive and 13 remained on treatment. 1 patient achieved complete response (CR) for target lesions, 8 partial response (PR), 14 stable disease (SD), illustrating an ORR of 29% and a DCR of 74.2%. Median PFS was 8.8 months (95%CI:5.868-11.732). The most common treatment-related adverse events (TRAEs) were proteinuria (35.5%), hypertension (22.6%) and rash (19.4%). Grade 3-4 AEs occurred in 9 patients, including proteinuria and hypertension, and there were no treatment-related deaths. Conclusions: SABR combined with tislelizumab and fruquintinib shows promising effects and good safety in the treatment of metastatic colorectal cancer, which is expected to provide new therapeutic strategies and improve the prognosis for mCRC patients. Clinical trial information: NCT04948034 . [Table: see text]

Neoadjuvant nivolumab plus paclitaxel/cisplatin- chemo-radiotherapy (neo-NTP-CRT) followed by esophagectomy for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II study.

e16098 Background: Adjuvant nivolumab has shown efficacy in reducing recurrence in patients (pts) with locoregional esophageal cancer harboring pathologic residual disease following neoadjuvant chemoradiotherapy (CRT). However, the efficacy of adding nivolumab to neoadjuvant CRT remains unclear. Methods: We conducted a phase II trial of neoadjuvant nivolumab (240mg IV on D-14, 1, 15, 29), paclitaxel (50mg/m2 IV on D1, 8, 15, 22, 29), cisplatin (30mg/m2 IV on D1, 8, 15, 22, 29) and RT (45Gy given in 25 fractions) followed by esophagectomy 6 to 8 weeks after finishing CRT in pts with locally advanced ESCC, defined as clinical stage cT3-4aN0M0 or cT1-3N1-3M0 according to the AJCC Cancer Staging System 8th ed. (ClinicalTrials.gov Identifier: NCT05130684). The study, in a Simon’s two-stage design, used pathological complete response (pCR) rate as the primary endpoint. Secondary endpoints included feasibility, safety, recurrence free survival (RFS), progression free survival (PFS), and overall survival (OS). Results: Between Jan 2021 and Apr 2023, we enrolled a total of 17 pts. Fifteen were male. The median age was 52 years (range: 44~69). The clinical stage was I, II, and III in 1, 1, and 15 pts, respectively. All pts received neo-NTP-CRT with the following dose-intensities (mean dose intensity [range]): nivolumab (95% [50%~ 100%]), paclitaxel (75% [48%~ 100%], cisplatin (97% [80%~ 100%]), and radiotherapy (100%). Fourteen pts received esophagectomy, and 4 of them achieved pCR (24%). Because pCR for the first stage did not meet the efficacy criteria to move forward to second-stage, the enrollment was discontinued after enrolling 17 pts. During neo-NTP-CRT, the most common treatment-related adverse events (TRAEs) were leukopenia (76%), neutropenia (59%), thrombocytopenia (35%), and skin rash (35%); and the most common grade 3 and 4 TRAEs were leukopenia (24%), neutropenia (6%), and nausea and vomiting (6%). Among 14 pts receiving esophagectomy, 4 experienced surgical complications, including 2 with anastomotic leakage, 1 with subclavian artery rupture, and 1 with pneumonitis; one pt died 263 days after surgery, followed by a prolonged hospital stay due to refractory anastomotic leakage, infectious complications, and tumor progression. The median follow-up duration was 18 months. Median RFS, PFS and OS was 8, 12, and 16 months, respectively. Conclusions: Our data indicate that adding nivolumab to neoadjuvant paclitaxel and cisplatin-based CRT is feasible but does not improve pCR rate in locally advanced ESCC pts. Clinical trial information: NCT05130684 .

Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment.

4018 Background: In first line of advanced biliary tract cancer (BTC), immune-checkpoint inhibitor (ICI) in combination with cytotoxic chemotherapy is now standard of care supported by TOPAZ-1 and KN-966 studies. With this landscape, new drug development using ICI in second or later line setting is urgent unmet medical needs area. Anti-angiogenic agent induced improved anti-tumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. Methods: This study is an open-label, phase 2 trial to investigate the efficacy of sitravatinib and tislelizumab (PD1 inhibitor) combination treatment for 2L advanced BTC. Patients who received prior ICI could be enrolled. All patients received sitravatinib 120mg orally once daily in combination with tislelizumab 200mg intravenously once every 3 weeks until disease progression, unacceptable toxicity. The primary endpoint was disease control rate (DCR), with key secondary endpoints including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Tissue biopsies were conducted three times in total: screening, the first response evaluation, and disease progression. Blood samples were collected every cycles. (NCT04727996) Results: A total of 43 patients were enrolled. Data-cut off was on July 31, 2023. Median follow-up was 10.5months (95% Confidence interval (CI), 7.03-15.6). 9 patients had received prior ICI. This study met primary endpoint as a DCR of 65.1% in all population. ORR was 20.5% in unselected per-protocol population, and PFS was 4.93 months (95% CI, 3.10-8.87). OS was 10.3months (95% CI, 6.67-18.2). Similar efficacy was observed regardless of prior ICI exposure. The most common treatment-related adverse events (AEs) were sitravatinib-related; hand-foot syndrome (any grade 60.5%, grade 3/4 0%), hypertension (any grade 34.9%, grade 3/4 11.6%). Immune-related AEs (irAEs) were 46.5%, with most irAEs being grade 1-2. In exploratory analysis, patients with homologous recombination deficiency (HRD) detected by baseline tissue NGS (frequency 18.5%) showed higher ORR (60% vs 13.6%), longer PFS (not reached vs 4.87 months) and OS (21.1 vs 8.57 months) than patients without HRD. HRD detected by circulating tumor DNA had a complementary role for patient selection. RNA sequencing showed upregulation in inflammatory signal and downregulation in angiogenesis signal between screening and on-treatment tumor tissue. Responders showed higher inflammatory signaling at baseline and on-treatment tumor tissue compared to non-responders. Conclusions: Sitravatinib/tiselizumab combination as 2L therapy in patients with advanced BTC demonstrated meaningful efficacy and an acceptable safety profile. Especially, patient selection using HRD biomarker might be a promising strategy in this setting. Clinical trial information: NCT04727996 .