Objective Tumor Response Rate Research Articles

A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1.

TPS3165 Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (DXd). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Methods: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll up to 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid TA-MUC1-expressing tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS-3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Clinical trial information: NCT05875168 .

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.

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.

A proof-of-concept study of LXP5268 as an add-on neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer.

e12607 Background: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype characterized by a high risk of mortality and a poor prognosis. The 2019 ASCO and St. Gallen International Consensus Guidelines strongly recommend neoadjuvant chemotherapy (NACT) for early-stage TNBC. Previous studies indicated that NACT improved overall and disease-free survival in early-stage TNBC. LXP5268, a drug in the 505(b)(2) category, has demonstrated efficacy in reducing tumor size in animal models. Our study aims to assess whether combining LXP5268 with NACT enhances anti-tumor efficacy and tumor shrinkage rates in early-stage TNBC patients. Methods: Enrolled patients had untreated stage II-III TNBC. NACT consisted of docetaxel every 3 weeks for four cycles, followed by epirubicin plus cyclophosphamide every 3 weeks for an additional four cycles (24 weeks total). In the LXP5268 add-on NACT (LXP5268+NACT) group, patients took LXP5268 orally once daily with NACT. After treatment, we analyzed tumor objective response rate (ORR), shrinkage rate by CT images, and adverse events (AEs) diagnosed by the principal investigator. Whole-exome sequencing (WES) was performed on 6 subjects in the LXP5268+NACT group, identifying potential germline variants and biomarkers, clinically interpreted following ACMG/AMP 2015 guidelines. Results: Both groups had similar baseline characteristics. LXP5268+NACT subjects (54.8 ± 7.2 years) and NACT subjects (59.3 ± 9.8 years) showed significant age differences ( p<0.001). The ORR was 100% in both the LXP5268+NACT group (3 pathological complete response, pCR and 4 pathological partial response, pPR) and NACT group (6 pPR). The tumor shrinkage rate was significantly higher in the LXP5268+NACT group at 77.3% ± 21.8 compared to 43.4% ± 12.8 in the NACT group ( p< 0.001). Moreover, subjects in the LXP5268+NACT group with a tumor reduction exceeding 50% surpassed those in the NACT group. AEs included neutropenia (85.7%), constipation (66.7%), and insomnia (66.7%), all grade 1. Interestingly, mutation in XIRP2 correlated with higher tumor shrinkage rate. Conclusions: LXP5268 combined with NACT was more effective than NACT alone for early-stage TNBC, without increasing AEs. These results highlight LXP5268's potential in TNBC therapy. Previous studies indicated XIRP2 mutations in metastatic breast cancer. LXP5268+NACT achieved pCR in XIRP2-mutated patients. Future clinical trials will expand to enhance result verification accuracy. Clinical trial information: CMUH106-REC3-145.

Abstract CT291: A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1

Abstract Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (deruxtecan [DXd]). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Trial design: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll a maximum of 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Citation Format: Noboru Yamamoto, Toshihiko Doi, Manish R. Patel, Ignacio Garrido-Laguna, Sutun Wu, Satoshi Nishioka, Keiko Nakajima, Benedito A. Carneiro. A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT291.

Recombinant human adenovirus p53 combined with transcatheter arterial chemoembolization for liver cancer: A meta-analysis.

To compare the clinical curative effects, survival and complications of recombinant human adenovirus-p53 (rAd-p53) combined with transcatheter arterial chemoembolization (TACE) versus TACE for the treatment of liver cancer. We searched all the eligible studies of rAd-p53 plus TACE versus control group had only TACE in the treatment of liver cancer, which were retrieved from CNKI, Wanfang database, CBM, VIP, PubMed, EMBase, The Chrance of Library, Web of Science from its inception to august 2022. A total of 17 studies were included, which involved 1045 patients. The results of the meta analysis indicated that the the rAd-p53combined with TACE markedly improved the patients' complete remission(OR = 2.19, 95% CI:1.13-4.22, P = 0.02), partial remission (OR = 2.22, 95% CI:1.67-2.94, P<0.00001), objective tumor response rate (OR = 2.58, 95% CI:1.95-3.41, P<0.00001) and disease control rate(OR = 2.39, 95% CI:1.65-3.47, P<0.00001) compared with TACE alone. And our results showed that rAd-p53combined with TACE had better survival benefit [6-month OS (OR = 3.41, 95% CI: 1.62-7.14, p = 0.001); 1-year OS (OR = 1.95, 95% CI: 1.28-2.96, p = 0.002)] and better quality of life(MD = 5.84, 95% CI:2.09-9.60, P = 0.002). In addition, the immunity of the patients was enhanced by the combination therapy, as demonstrated by the increase in the ratio of CD4+ to CD4+/CD8+. In adverse effects, except for fever in the TACE combined with rAd-p53 group, which was higher than that in the TACE group(OR = 2.62, 95% CI:2.02-3.49, P<0.00001), all other adverse effects were lower in the TACE combined with rAd-p53 group than in the TACE group. RAd-p53 combined with TACE for liver cancer showed significant advantages in terms of clinical efficacy, survival rate, and safety compared to the TACE alone, and effectively improved patient quality of life and immune function. https://inplasy.com/inplasy-2022-9-0127/.

Evidence and possible mechanism of Scutellaria baicalensis and its bioactive compounds for hepatocellular carcinoma treatment

Background Traditional Chinese medicines have been reported to have outstanding effects in the treating of hepatocellular carcinoma. Scutellaria baicalensis (S. baicalensis) has demonstrated anti-tumor, anti-angiogenic, and anti-inflammatory properties. Baicalein, wogonin, and baicalin are the main pharmacologically bioactive compounds of S. baicalensis. Methods Eight electronic databases were searched to select articles published from their inception to 30 May 2022. For selected articles, clinical and preclinical data was obtained on the use of S. baicalensis and its bioactive compounds in hepatocellular carcinoma therapy. Statistical analyses were performed using RevMan version 5.3 and Stata software. Quality assessment of the studies was performed using Cochrane and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)’s risk of bias tools. Results Seven clinical and 17 preclinical in vivo studies along with 31 in vitro studies were included in this research. Meta-analysis showed that a Chinese herbal medicine preparation, with S. baicalensis as the sovereign herb, combined with Transcatheter arterial chemoembolization (TACE) or primary treatment, could lead to a significantly improved tumor objective response rate (Risk ratio (RR) = 1.57, 95% confidence interval (CI): [1.30, 1.90], p < 0.00001). Scutellaria baicalensis-based extracts (standard mean difference (SMD) = –0.86, 95%CI: [–1.20, −0.53], p < 0.00001), baicalein (SMD = –4.80, 95%CI: [–6.66, − 2.95], p < 0.00001), baicalin (SMD = –2.28, 95%CI [–3.26, −1.30], p < 0.00001) and wogonin (SMD = –1.41, 95%CI [–2.26, −0.57], p < 0.00001) slowed tumor growth in vivo. These outcomes might be linked to the mechanism by which S. baicalensis promotes apoptosis, induces autophagy, and blocks the expression of vascular endothelial growth factor (p < 0.05). Conclusion Based on experimental and clinical evidence, we believe that S. baicalensis and its bioactive compounds have therapeutic potential and plausible mechanisms of action against hepatocellular carcinoma, in terms of efficacy and safety.

Efficacy and safety of Xiao-ai-ping injection add-on therapy to chemotherapy in patients with non-small cell lung cancer: A systematic review and meta-analysis.

Xiao-ai-ping injection (XAPI) combined with chemotherapy has potential efficacy and less side effects in the treatment of non-small cell lung cancer (NSCLC). At present, there are many clinical studies on XAPI combined with chemotherapy in the treatment of NSCLC, but the results are different. The purpose of this study was to evaluate the efficacy and safety of XAPI combined with chemotherapy in the treatment of NSCLC by meta-analysis system. The databases to be searched include PubMed, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang database, Chinese Scientific Journal Database, and so on. In addition, relevant journals and magazines will manually search in various fields as supplements. The search date is set from the establishment of the database until July 8, 2023. The 2 researchers will use Endnote X9 software for literature screening and data extraction and independently evaluate the quality. We then assessed the quality and risk of inclusion in the study and observed outcome indicators. A total of 28 trials were included in this study, 1947 patients with NSCLC (974 receiving XAPI combined chemotherapy and 973 receiving chemotherapy alone). The results of meta-analysis showed that: Objective tumor response rate of NSCLC (P < .00001). Improvement in Karnofsky performance score of NSCLC (P < .00001). Quality of life score of NSCLC (P < .00001). The result of CD3 + (P < .00001). The result of CD4 + (P < .00001). The result of CD8 + (P < .00001). The result of CD4+/CD8 + (P = .0001). Leukopenia (P < .00001). Thrombocytopenia (P < .00001). Hemoglobin decrease (P < .00001). Liver function (P = .04). Nausea and vomiting (P < .00001). Our meta-analyses demonstrated that XAPI adjunct with chemotherapy can improve the patient quality of life, reduce adverse reactions, and enhanced immune function, the treatment is effective and high safety. Which suggests that it might be used for NSCLC. However, a large sample of randomized controlled trials are needed to further study the long-term efficacy of XAPI.

Transarterial Chemoembolization Plus Lenvatinib and PD-1 Inhibitors for Hepatocellular Carcinoma with Main Trunk Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

In recent years, immune checkpoint inhibitors have been used in combination with tyrosine kinase inhibitors and local therapies, creating a new era in treating hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). However, the benefits of this triple therapy remain unclear. Thus, this study evaluated whether the combination of transarterial chemoembolization (TACE), lenvatinib, and programmed death-1 (PD-1) inhibitors (triple therapy) was effective and safe for unresectable HCC with main trunk portal vein tumor thrombus (Vp4). This study enrolled patients receiving triple therapy at four institutions between August 2018 and April 2022. Patient characteristics and course of treatment were extracted from patient records. Tumors and tumor thrombus response were evaluated using an HCC-specific modified RECIST. Kaplan-Meier curve analysis demonstrated overall survival (OS) and progression-free survival (PFS). Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Median follow-up duration was 18 (4.0-26.3) months. Overall, 41 patients with HCC and Vp4 receiving first-line triple therapy were enrolled. The intrahepatic tumor objective response rate was 68.3%. The median OS was 21.7 (range, 2.8-30.5) months, whereas the median PFS was 14.5 (range, 1.3-27.6) months. Twelve patients received sequential resections. Resection was independently associated with favorable OS and PFS. Fever (31.7%), hypertension (26.8%), fatigue (24.4%), abnormal liver function (63.4%) and decreased appetite (21.9%) were the AEs frequently associated with treatment. No treatment-related mortality occurred. TACE plus lenvatinib and PD-1 inhibition was effective and tolerable for treating unresectable HCC with Vp4, with a high tumor response rate and favorable prognosis.

Quality of life, effectiveness, and safety of aflibercept plus FOLFIRI in older patients with metastatic colorectal cancer: An analysis of the prospective QoLiTrap study

IntroductionColorectal cancer (CRC) mainly affects older patients. The pivotal VELOUR phase III trial of aflibercept plus FOLFIRI in metastatic CRC (mCRC) included only 5.9% of patients aged ≥75 years. Herein, we report a preplanned analysis from QoLiTrap, a large prospective observational study evaluating the impact of age on quality of life (QoL), effectiveness, and safety of aflibercept plus FOLFIRI in daily clinical practice in Europe. Materials and MethodsEnrolled patients had progressive mCRC, had failed a prior oxaliplatin-based regimen, and had received aflibercept (4 mg/kg) plus FOLFIRI every two weeks until disease progression, death, unacceptable toxicity, or physician/patient decision. Analyses were performed by age classes (<60, 60–64, 65–69, 70–74, and ≥ 75 years). The primary endpoint was the percentage of patients whose global health status (GHS) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was maintained (i.e., no worsening from baseline by at least 5% over a 12-week treatment). Secondary endpoints included tumor objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. ResultsOverall, 1277 patients (<60 years, n = 327; 60–64 years, n = 231; 65–69 years, n = 227; 70–74 years, n = 259; and ≥ 75 years, n = 233) were treated, of whom 872 were evaluable for QoL. GHS was maintained in 36.5%, 41.6%, 38.9%, 41.8%, and 44.8% of patients aged <60, 60–64, 65–69, 70–74, and ≥ 75 years, respectively. Age did not influence PFS (median 7.8 months), OS (median 14.4 months), or ORR (20.8%). Number of cycles, dose delays for any cause, and dose reductions for adverse events (AEs) were comparable between age classes. Grade ≥ 3 AEs occurred in 47.7%, 51.9%, 51.5%, 55.2%, and 55.8% of patients aged <60, 60–64, 65–69, 70–74, and ≥ 75 years, respectively. The main grade ≥ 3 AEs were hypertension (11.2%) and diarrhea (9%) in patients aged ≥75 years. DiscussionThe results suggest that aflibercept plus FOLFIRI maintains QoL and retains its activity, including a high objective tumor response, regardless of age and treatment line. In fit older patients, the safety profile seems manageable, with no new safety signals.

Drug-eluting beads versus conventional transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis.

Transarterial chemoembolization (TACE) consists of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE). The benefits of the 2 treatments remain controversial. We conduct this meta-analysis to assess the efficacy and safety of the 2 methods for the patients with unresectable hepatocellular carcinoma. In order to get a sound conclusion, we did thorough search all relevant studies with clear and stringent keyword criteria on the main databases. Objective tumor response rate, overall survival (OS) rate and adverse events were calculated and analyzed by RevMan 5.3 software. The random-effects or fixed-effects model was applied to pool the estimates according to Cochran Q test and I2 statistics. Twenty-four studies involving 2987 patients were eligible. DEB-TACE significantly improved objective tumor response rate (OR) (risk ratio [RR] = 1.27, 95% confidence interval [CI] [1.08, 1.48]; P = .003). While as for 1-year, 2-year, 3-year, 5-year OS rates, there were no evidences to indicate that DEB-TACE was significantly better than cTACE (RR = 1.05, 95% CI [0.99, 1.11]; P = .08), (RR = 1.02, 95% CI [0.93, 1.11]; P = .68), (RR = 0.92, 95% CI [0.77, 1.10]; P = .37), (RR = 0.92, 95% CI [0.47, 1.80]; P = .81), respectively. Adverse events rate (AE) was also similar in both groups (RR = 1.11, 95% CI [0.99,1.26]; P = .08). This meta-analysis demonstrates that DEB-TACE is not superior than cTACE regarding to OS and AE. However, DEB-TACE still be considered to provide a better objective tumor response rate for patients with unresectable hepatocellular carcinoma.

Tumor to liver maximum standardized uptake value ratio of FDG-PET/CT parameters predicts tumor treatment response and survival of stage III non-small cell lung cancer

BackgroundTo assess the predictive values of primary tumor FDG uptake for patients with inoperable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT).MethodsA total of 107 patients with diagnosis of stage III NSCLC and CCRT were enrolled. The tumor maximum uptake value (SUVmax) was standardized by calculating several ratios between tumor and each background tissues. The receiver operating characteristics curve (ROC) was used to compare the predictive power of prognostic models. The tumor objective response rate (ORR) and overall survival (OS) were compared and analyzed by the Kaplan–Meier method and univariate and multivariate Cox regression models.ResultsThe areas under ROC curve (AUCs) ranged from 0.72 to 0.81 among these tumor SUVmax and standardized SUVmax ratios, and the tumor SUVmax and tumor SUVmax-to-liver SUVmean ratio (TLMR) were more predictive of ORR (AUC, 0.81; 95% CI, 0.73–0.88 for tumor SUVmax and AUC, 0.84; 95%CI, 0.76–0.91 for TLMR) than any of other SUVmax ratios. The patients with lower tumor SUVmax, SUVmean and SUVmax ratios had a significantly better OS than those with their corresponding higher ones. Moreover, both univariate and multivariable analyses revealed that TLMR was significantly associated with better ORR and OS after adjustment with other prognostic variables.ConclusionsTLMR, a standardized tumor SUVmax, was an independent prognostic predictor for tumor ORR and OS of patients with stage III NSCLC after CCRT.

Efficacy of transarterial therapy combined with first-line tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: a network meta-analysis

BackgroundTransarterial therapies, including transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and selective internal radiation therapy, combined with first-line tyrosine kinase inhibitors (TKIs) are considered the standard therapy for unresectable hepatocellular carcinoma. However, inconsistent results have been reported in various studies assessing different combinations of targeted agents.MethodsA network meta-analysis (NMA) was performed by including 23 randomized controlled trials (RCTs) with 6175 patients to investigate the efficiency of transarterial therapies in combination with different TKIs. Outcomes of interest included overall survival (OS), progression-free survival (PFS), time to progression (TTP), and tumor objective response rate (ORR). A random-effects consistency model was used in this Bayesian NMA. Hazard ratio and odd risks with a 95% credible interval were calculated and agents were ranked based on ranking probability.ResultsHAIC showed maximal OS and TTP and TACE plus lenvatinib showed maximal PFS, ORR, and disease control rate (DCR). HAIC and TACE plus lenvatinib were ranked highest based on their respective parameters, which were OS for HAIC and PFS, ORR, and DCR for TACE plus lenvatinib.ConclusionHAIC and TACE plus lenvatinib were relatively better choice for unresectable hepatocellular carcinoma. However, owing to the lack of statistically significant OS benefits among most agents, other agents should be considered as potential alternatives for unresectable hepatocellular carcinoma.

Intermediate-stage (BCLC stage B) infiltrative hepatocellular carcinoma: safety and efficacy of chemoembolization.

To evaluate the safety and efficacy of chemoembolization in patients with intermediate-stage infiltrative Hepatocellular carcinoma (HCC). This retrospective study evaluated outcomes in treatment-naïve patients who received chemoembolization as first-line treatment for intermediate-stage infiltrative HCC between 2002 and 2022. Of the 2029 treatment-naïve patients who received chemoembolization as first-line treatment for intermediate-stage HCC, 244 (12%) were identified as having the infiltrative type. After excluding two patients lost to follow-up, 242 patients were evaluated. Median post-chemoembolization overall survival (OS) was 16months. Multivariable Cox analysis identified four factors predictive of OS: Child-Pugh class B (hazard ratio [HR], 1.84; p = 0.001), maximal tumor size ≥ 10cm (HR, 1.67; p < 0.001), tumor number ≥ 4 (HR, 1.42; p = 0.037), and bilobar tumor involvement (HR, 1.64; p = 0.003). These four factors were used to create pretreatment prediction models, with risk scores of 0-1, 2-4, and 5-7 defined as low, intermediate, and high risk, respectively. Median OS times in these three groups were 34, 18, and 8months, respectively (p < 0.001). The objective tumor response rate following chemoembolization was 53%. The major complication rate was 9% overall and was significantly higher in the high-risk group (22%) than in the low (2%) and intermediate (3%) risk groups (p < 0.001). Chemoembolization is safe and effective in selected patients with intermediate-stage infiltrative HCC. Chemoembolization is not recommended in high-risk patients with intermediate-stage infiltrative HCC because of poor OS and high rates of major complications. A pretreatment prediction model was developed using four risk factors associated with overall survival following chemoembolization for intermediate-stage infiltrative hepatocellular carcinoma. This model may provide valuable information for clinical decision-making. • Four risk factors (Child-Pugh score B, maximal tumor size ≥ 10cm, tumor number ≥ 4, and bilobar tumor involvement) were used to create pretreatment prediction models, with risk scores of 0-1, 2-4, and 5-7 defined as low, intermediate, and high risk, respectively. • Median overall survival (OS) times and major complication rate in these three groups were 34, 18, and 8months, and 2%, 3%, and 22%, respectively (p < 0.001). Chemoembolization is not recommended in high-risk patients with intermediate-stage infiltrative Hepatocellular carcinoma (HCC) because of poor OS and high rates of major complications.

Transarterial chemoembolization for liver metastases of a pancreatic neuroendocrine neoplasm: a single-center experience.

Transarterial chemoembolization (TACE) is performed for pancreatic neuroendocrine tumor (PanNEN) liver metastases; however, the safety and efficacy of TACE procedures, especially for patients who have undergone previous pancreatic surgery, have not been established. We reviewed 48 TACE procedures (1-6 procedures/patient) performed on 11 patients with PanNEN liver metastases, including 16 TACE procedures (4-6 procedures/patient) for 3 patients with a history of biliary-enteric anastomosis. The overall tumor objective response rate was 94%. The incidence of Clavien‒Dindo grade ≥ 2 complications was 1/16 (6%) and 1/32 (3%), and the median time to untreatable progression was 31 (14-41) and 27 (2-60) months among patients with and without a history of biliary-enteric anastomosis, respectively. Although validation is needed in future studies, our experiences have shown that TACE treatment is a viable treatment option for PanNEN liver metastases, even after biliary-enteric anastomosis with experienced teams and careful patient follow-up.

Olaparib in HR-deficient (HRD), metastatic triple-negative breast cancer (TNBC) and relapsed ovarian cancer (ROC) without germline mutations in BRCA1 or BRCA2: Phase 2 EMBRACE trial.

e15079 Background: Homologous recombination deficiency (HRD) caused by germline BRCA1/2 mutations (gBRCAm) sensitize high grade serous ovarian cancers (HGSOC) and TNBC to PARP inhibitors (PARPi) such as olaparib. Loss of function of BRCA1 or RAD51C, due to promoter methylation or mutation of non-BRCA HR genes may also confer sensitivity to PARPi. This investigator-initiated, proof-of-concept trial evaluated olaparib in platinum(Pt)-sensitive, relapsed HGSOC and metastatic TNBC, with HRD due to mechanisms other than gBRCAm. EMBRACE is the first trial evaluating PARPi in loss of function of BRCA1/ RAD51C by promoter methylation. Methods: Single-arm, phase 2 trial of olaparib 300 mg orally twice daily in adults with metastatic TNBC or Pt-sensitive relapsed HGSOC and HRD due to mechanisms other than gBRCAm. 1 line of prior Pt-chemotherapy was allowed (HGSOC); additional lines of non-Pt therapy were allowed (TNBC). Tumor BRCA1/RAD51C promoter methylation was determined by methylation-sensitive high-resolution melting PCR and next generation sequencing (NGS, Pillar Biosciences BRCA1 &amp; RAD51C Methylation test, high methylation threshold 70%). Unmethylated cases underwent NGS HR gene mutation testing (Pillar Biosciences HRD test, paired tumor/normal). The primary outcome was objective tumor response rate (OTRR) at 6 months(m). Secondary objectives: progression-free survival (PFS), OTRR according to HR gene mutation type, safety. Tertiary: associations between biomarkers and clinical outcomes. Results: 22 participants (15 HGSOC, 7 TNBC) enrolled from 208 screened (Sep 2018 - Mar 2022). Methylation was detected in 8/15 HGSOC (all BRCA1) and 5/7 TNBC (4 BRCA1, 1 RAD51C). Both cohorts included mutations in gBRIP1 (1), gPALB2 (1), gRAD51C (3), sBRCA1 (2), with 1 COSMIC mutational signature 3, and 1 positive HRD score in HGSOC. OTRR at 6m was 40% in HGSOC (6/15: 5 partial, 1 complete), and 0% in TNBC (0/7). OTRR was 38% (3/8) in methylated tumors vs 43% (4/7) with other HRD. Stable disease at 6m was 47% (7) in HGSOC and 43% (3) in TNBC durations were 7m in HGSOC and 3m in TNBC. PFS was 53% at 6m and 25% at 12m in HGSOC, vs 17% at 6m and NE at 12m in TNBC. TNBC 2-3 prior lines of therapy. Conclusions: Olaparib demonstrated clinically relevant activity in HGSOC without gBRCAm. Objective responses were seen in HGSOC with methylated BRCA1. Olaparib had limited activity in heavily pre-treated TNBC. Further research is needed into the effects of non-Pt chemotherapy on methylation of BRCA1/RAD51C to improve selection of HGSOC and TNBC for PARPi. (ANZCTRN12617000855325) Acknowledgements: Funding from Cancer Australia and the NBCF(PS-15-048), provision of study drug plus an untied educational grant from AstraZeneca and its group of companies. EMBRACE was led by the NHMRC CTC, University of Sydney in collaboration with ANZGOG, BCT-ANZ, and GCCTI. Clinical trial information: ACTRN12617000855325 .

Six-year safety and efficacy results from the CHRONOS-1 study of the PI3K inhibitor copanlisib in patients with relapsed or refractory follicular lymphoma.

7555 Background: The efficacy of copanlisib, an intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, was demonstrated in the Phase II CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma (Dreyling et al. J Clin Oncol 2017). Copanlisib was approved by the US Food and Drug Administration in 2017 for the treatment of patients with follicular lymphoma (FL) who have received ≥2 therapies. Here, we describe updated efficacy and safety data from patients with FL at the 6-year follow-up of CHRONOS-1. Methods: CHRONOS-1 included patients with relapsed or refractory indolent FL (grades 1-3a) who had received ≥2 lines of therapy. Copanlisib 60 mg was administered via intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Objective tumor response rate (ORR) was assessed by independent radiologic review (Cheson et al. J Clin Oncol 2007) as the primary efficacy endpoint. Safety analysis included adverse events graded using CTCAE v4.03. Results: 104 patients with FL were treated in CHRONOS-1, of whom 99.0% ( n= 103) discontinued treatment at the time of database cut-off on June 30, 2022. 72% of patients ( n= 75) received ≥1 line of subsequent systemic anti-cancer therapy during follow-up, with 40% receiving a rituximab-based regimen. At the cut-off, ORR (primary endpoint) was 57.7% ( n= 60), with 19.2% ( n= 20) of patients achieving a complete response. Median duration of response was 12.2 months (range 1.1-48.1). Median progression-free survival (PFS) was 11.2 months (range 0.2-51.5) with a median follow-up of 20.7 months (95% confidence interval [CI] 11.5, 31.5); PFS rate was 32% at 2 years. Median overall survival was 46.3 months (range 0.7-82.9) with a total of 56 events and a median follow-up of 82.4 months (95% CI 79.3, 84.9); survival rate was 43% at 6 years. Median duration of treatment was 6.0 months (range 0.23-80.9). No patients experienced transformation to aggressive lymphoma (diffuse large B-cell lymphoma). The primary reasons for stopping treatment included radiologic disease progression (42.3%; n= 44) and adverse events not associated with clinical disease progression (29.8%; n= 31). The safety profile was consistent with the reported 2-year follow-up data (Dreyling et al. Am J Hematol 2020). The most common treatment-emergent adverse events (all grades/grades 3-4) were infusion-related hyperglycemia (50.0%/39.5%), diarrhea (36.5%/8.7%), hypertension (28.8%/23.1%), pyrexia (27.9%/4.8%), and neutropenia (26.0%/23.0%). Conclusions: Copanlisib continued to induce robust response and durable survival in patients with relapsed or refractory indolent FL at 6 years of follow-up. Copanlisib was well tolerated, with no new safety signals and no evidence of malignant transformation. These results further support the long-term use of copanlisib in this patient population. Clinical trial information: NCT01660451 .

Phase 1/2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors.

e17546 Background: ARTS-021 is an investigational, reversible, orally available CDK2 selective inhibitor that inhibits CDK2 at nanomolar potency and with over 600-fold selectivity against CDK1 (Liang J et al. AACR 2022). ARTS-021 has shown promising preclinical data, including strong single agent antitumor activity in CCNE1 amplified patient derived xenografts (PDX). Furthermore, consistent with the hypothesis that CDK2 activity may mediate resistance to CDK4/6 inhibitors, ARTS-021 significantly enhanced Palbociclib anti-tumor activity in an estrogen positive (ER+) breast cancer xenograft model. Taken together, these data support the clinical development of ARTS-021 as a monotherapy in CCNE1-amplified cancers and in combination with CDK4/6 inhibitors in ER+ breast cancer. Methods: A first in human, open label, multicenter phase1/2 dose escalation and dose expansion study will be conducted to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and anti-tumor activity of ARTS-021 1) as a single agent in advanced or metastatic solid tumors harboring CCNE-1 gene amplification; 2) in combination with carboplatin to treat refractory/resistant CCNE-1 amplified ovarian cancer that has failed standard therapies; 3) in combination with endocrine therapy and CDK4/6 inhibitor to treat ER+/HER2- breast cancer patients have failed standard therapies. The phase 1 (dose-escalation) portion of the trial will have an accelerated dose escalation followed by a Bayesian Optimal Interval (BOIN) design. After the monotherapy recommended phase 2 dose (R2PD) is identified, the combination arms will be initiated at one dose level below the monotherapy R2PD. Phase1 primary endpoints are assessment of safety, tolerability, and pharmacokinetics (PK). The secondary endpoint is preliminary efficacy. Once the RP2D is defined for both monotherapy and in combination, the trial will be advanced into three Phase 2 expansion cohorts: monotherapy cohort (basket cohort), combination with carboplatin (ovarian cohort), and combination with endocrine therapy + CDK4/6 inhibitor (ER+ breast cancer cohort). The phase 2 primary end point is to estimate the anti-tumor efficacy in CCNE1 amplified cancer patients or CDK4/6 inhibitor resistant breast cancer patients. Objective tumor response rate will be measured per RECIST v1.1. The secondary endpoint of Phase 2 study will be safety/tolerability. Archival tumor and paired fresh tumor biopsy will be collected throughout the study for exploratory pharmacodynamics (PD) and biomarker evaluation. Results: ARTS-021 clinical study is ongoing. Conclusions: ARTS-021 shows potential anti-tumor activities.

The impact of cause of mismatch repair deficiency and other molecular markers on clinical outcomes with the use of durvalumab in advanced endometrial cancer in the phase 2 PHAEDRA trial (ANZGOG1601).

5604 Background: In the single arm phase 2 PHAEDRA trial, MMR deficiency (dMMR) was predictive of response to durvalumab (1500mg IV Q4W), with an objective tumor response rate (OTR; defined by iRECIST) of 47% in dMMR compared with 3% in MMR-proficient (pMMR) advanced endometrial cancer (AEC). This substudy of the PHAEDRA trial investigates MMR molecular subtypes and other genomic tumor features and their correlation with treatment outcomes. Methods: Testing was performed to determine molecular subtypes of dMMR, including germline pathogenic variants in DNA MMR genes (Lynch syndrome), somatic biallelic MMR gene inactivation through somatic mutation and somatic hypermethylation of the MLH1 gene promoter. DNA from formalin-fixed paraffin-embedded tumor tissue and matched peripheral blood was available from 41/71 (25 dMMR, 16 pMMR) participants for testing on a custom capture-based 298-gene targeted panel (2.005Mb) including the MMR genes and key somatic AEC driver genes. The derived tumor genomic features included microsatellite instability (MSI), tumor mutational burden (TMB), COSMIC v.3.2 tumor mutational signatures and insertion/deletion (Indel) somatic mutation count. Results: Of the 71 patients recruited, 35 were dMMR and 36 were pMMR. Median follow-up was 44 vs 52 months in dMMR vs pMMR participants, respectively. The dMMR molecular subtypes were 4 (11.4%) Lynch syndrome, 4 (11.4%) somatic MMR mutation, 25 (71.4%) MLH1 methylated and 2 (5.7%) dMMR-uncategorised. The OTR rate was 100% (4/4; 95%CI 40-100%) for Lynch, 75% (3/4; 95%CI 22-99%) for somatic MMR mutations and 40% (10/25; 95%CI 22-61%) for MLH1 methylated groups. The median TMB (assessed in 41/71) was higher in those with a confirmed radiological response (37, IQR:26-50) vs non-responders (16, IQR:9-25; p &lt; 0.001). Within the MLH1 methylated group, TMB was also higher in responders vs non-responders (40 v 21; p = 0.03). Somatic mutations in KRAS, PTEN, PIK3CA, ARID1A and TP53 were not associated with OTR rate. Conclusions: dMMR- MLH1 methylated AEC demonstrated greater heterogeneity in OTR to single agent durvalumab than the dMMR-Lynch and dMMR-somatic MMR mutation molecular subtypes. Higher TMB was seen in responders, and specifically within dMMR- MLH1 methylated responders, compared to non-responders. Clinical trial information: ANZGOG1601.

Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non-small cell lung cancer.

In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC). The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration. A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4months (95% CI, 3.4-19.8months) and 3.0months (95% CI, 1.7-5.7months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%. Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. ClinicalTrials.gov identifier: NCT02419495. New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer.