Prolonged Progression-free Survival Research Articles

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study

The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up. COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791. Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation). First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. Exelixis and Ipsen.

Adverse Events of Cabozantinib as a Potential Prognostic Factor in Metastatic Renal Cell Carcinoma Patients: Real-World Experience in a Single-Center Retrospective Study.

Cabozantinib, an oral inhibitor targeting MET, AXL, and VEGF receptors, has become a key component of a sequential treatment strategy for clear cell renal cell carcinoma (ccRCC). The purpose of this work is to show that effective management of adverse events (AEs) during cabozantinib treatment and achieving a balance between AEs and treatment efficacy is crucial to achieving therapeutic goals. In this retrospective study, involving seventy-one metastatic RCC (mRCC) patients receiving second or subsequent lines of cabozantinib at the Department of Genitourinary Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, we explored the impact of AEs on overall survival (OS) and progression-free survival (PFS). AEs were observed in 92% of patients. Hypothyroidism during treatment was significantly associated with prolonged OS and PFS (HR: 0.31; p < 0.001 and HR: 0.34; p < 0.001, respectively). The occurrence of hand-foot syndrome (HFS) was also linked to improved OS (HR: 0.46; p = 0.021). Patients experiencing multiple AEs demonstrated superior OS and PFS compared to those with one or no AEs (HR: 0.36; p < 0.001 and HR: 0.30; p < 0.001, respectively). Hypothyroidism and HFS serve as valuable predictive factors during cabozantinib treatment in ccRCC patients, indicating a more favorable prognosis.

Clinical features and outcomes of patients with acute myeloid leukemia: the single-center experience of 668 patients in China

ABSTRACT Objective To investigate efficacy and prognostic factors in the treatment of adult newly-diagnosed acute myeloid leukemia (AML) with or without allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Methods We retrospectively analyzed 668 patients with newly-diagnosed AML (non-M3 type) in the Department of Hematology at Shanghai Changhai Hospital from January 2012 to December 2021. Based on different induction chemotherapy regimens, patients were categorized into an IA (idarubicin, IDA + cytarabine, Ara-C) (3 + 7, regimen) group (n = 303) and a DA (daunorubicin, DNR + cytarabine, Ara-C) (3 + 7, regimen) group (n = 365) with or without allo-HSCT. Minimal residual disease (MRD), complete response (CR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse effects (AE) were analyzed and compared. Characteristics significantly associated with overall or progression-free survival (OS or PFS) upon univariate analysis were subsequently included in a Cox proportional hazard model. Results This study used data from 668 AML patients. After induction therapy, the CR rate in the IA group was 70.63% and ORR was 79.87%, which were significantly higher than those in the DA group (with a CR rate of 56.99% and an ORR of 70.14%) (P = 0.0002 and P = 0.0035, respectively). There were no significant differences in drug safety between the two chemotherapy regimens used in IA and DA (P > 0.05). The recurrence rate was lower in patients with an MRD < 0.001 than in patients with an MRD ≥ 0.001. A continuous negative MRD during the period is significant because it is associated with prolonged OS and PFS of AML patients. Data from 100 patients in the two groups who underwent allo-HSCT were analyzed using univariate analysis and the Cox proportional hazards model. From the multivariate analysis, MRD was found to be the only independent predictor of OS (P = 0.042; HR 1; 95%CI 0.00–0.76). Conclusion In the treatment of adult AML patients, IA regimen is associated with a high CR rate and ORR rate and does not increase treatment-related toxicity. IA regimen prolongs OS and PFS in AML patients and reduces the likelihood of leukemia cells’ subsequent infiltration into the central nervous system. There is a high correlation between the level of MRD after treatment and the patient's bone marrow recurrence. To obtain superior treatment effects for patients undergoing allo-HSCT, the MRD should be reduced to less than 0.001 before pretreatment. A negative MRD before allo-HSCT can prolong OS in patients with AML. We examined the clinical characteristics and outcomes of AML patients in China, finding novel information on prognostic factors and primary treatment of AML that may be applicable in routine clinical practice.

Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42-65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17months (2-86months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3-4 lymphopenia and grade 3-4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable.

PARP inhibitor maintenance treatment for newly diagnosed ovarian cancer patients: a real-world study from China.

This study evaluated the efficacy and safety in a real-world population of epithelial ovarian cancer (EOC) treated with poly (ADP-ribose) polymerase inhibitor (PARPi) as first-line maintenance therapy in the largest gynecologic oncology center in Western China. This study included patients newly diagnosed EOC who received PARPi as first-line maintenance therapy in West China Second University Hospital from August 1, 2018 to September 31, 2022. The primary endpoints were progression-free survival (PFS) and safety evaluated by Common Terminology Criteria for Adverse Events Version 5.0(CTCAE 5.0). The secondary endpoints were overall survival (OS) and prognostic factors influencing the PFS of patients in real world. Among the eligible 164 patients, 104 patients received olaparib and 60 patients received niraparib. 100 patients (61.0%) had mutations in breast cancer susceptibility gene (BRCA). 87 patients (53.0%) received primary debulking surgery (PDS) while 77 patients (47.0%) received interval debulking surgery (IDS). 94 patients (94/164, 57.3%) achieved R0 and 39 patients (23.8%) achieved R1 after PDS/IDS. 112 (68.3%) achieved complete response (CR) after first-line chemotherapy, while 49 (29.9%) achieved partial response (PR). The median follow-up time was 17.0 months (95% CI 15.6-18.4), and the median PFS has not been reached yet. Multivariate analysis demonstrated that BRCA mutations and CR/PR after platinum-based chemotherapy were independent factors associated with prolonged PFS. Hematologic toxicity was the most common grade≥3 AE. There were no incidence of myelodysplastic syndromes/acute myelogenous leukemia (MDS/AML). Focusing on PARPi as first-line maintenance therapy for patients with EOC, this study represented the largest single-center real-world study in China to date. Two independent factors were identified to prolong the PFS of patients: BRCA mutated type and CR/PR after primary treatment, which should be further confirmed with long-term follow-up and large sample sizes.

Efficacy and safety of combination of poly-ADP-ribose polymerase inhibitor (PARPi) and chemotherapy compared with chemotherapy alone in treatment of recurrent ovarian carcinoma: a systematic review.

Platinum-based chemotherapy after surgical cytoreduction is the universal treatment for advanced ovarian cancer (OC), however, about eighty percent of patients experienced relapse and progression-free survival remained poor. Patients who relapsed within one year of treatment eventually become resistant to second-line chemotherapy. Poly-ADP-ribose polymerase inhibitors are a novel class of targeted therapy that could overcome these challenges by augmenting the chemotherapeutic activity of other cytotoxic agents. Cumulative Index to Nursing and Allied Health Literature (CINHAL), Cochrane and PubMed databases were searched for potentially relevant primary publications from 2011 to 2022 reporting on efficacy and safety of combination of a PARP inhibitor and chemotherapy versus chemotherapy in recurrent OC and reviewed. The outcomes of interest assessed qualitatively were progression-free survival (PFS) and grade 3 or higher adverse events (AEs) as measures of efficacy and safety respectively. Eight randomized controlled trials (RCTs) were included in the systematic review comprising 3,021 patients evaluated efficacy and safety of PARP inhibitors: Olaparib, niraparib and veliparib with combinations of bevacizumab, carboplatin, cisplatin, cediranib, cyclophosphamide and paclitaxel. 824 patients had 33 BRCA mutation while 1,430 had wild-type BRCA, an allele that confers increased risk of cancer. Most patients had platinum-sensitive cancers. There was significant prolongation of PFS with PARP inhibitor and chemotherapy combination compared to chemotherapy in all included trials except one which combined veliparib with cyclophosphamide. The prolongation of PFS was more remarkable in patients with BRCA mutation and occasionally patients with wild-type BRCA. Niraparib and veliparib were notably associated with grade 3 or higher anaemia, neutropenia, and thrombocytopenia, olaparib caused fatigue and gastrointestinal disturbances while bevacizumab and cediranib caused hypertension. This review suggested combined PARP inhibitor and chemotherapy significantly prolonged progression-free survival especially in patients with BRCA mutation compared to chemotherapy and the combined therapy is safe.

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from the JAVELIN Bladder 100 trial in patients (pts) with high body mass index (BMI).

600 Background: Avelumab 1L maintenance is recommended as standard of care by international treatment guidelines for pts with aUC that has not progressed with 1L platinum-based chemotherapy, based on level 1 evidence from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). In the trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone (median OS, 23.8 vs 15.0 mo; HR, 0.76 [95% CI, 0.63-0.91]; 2-sided p=0.0036). The long-term safety of avelumab 1L maintenance was also demonstrated. It is estimated that 25% of the world’s population will have BMI ≥30 by 2035, and high BMI is a risk factor for bladder cancer. We report post hoc analyses of long-term outcomes from JAVELIN Bladder 100 in pts with high BMI (≥30) at baseline. Methods: Eligible pts with unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L platinum-based chemotherapy were randomized 1:1 to receive avelumab 10 mg/kg every 2 wk + BSC (n=350) or BSC alone (n=350). The primary endpoint was OS; secondary endpoints included PFS and safety. Results: At data cutoff (June 4, 2021), median follow-up was ≥38 mo in both arms. In the avelumab + BSC and BSC alone arms, 67 and 55 pts had high BMI at baseline, respectively. In these pts, median OS was 20.8 mo (95% CI, 16.9-34.4) with avelumab + BSC vs 12.7 mo (95% CI, 8.1-26.6) with BSC alone (HR, 0.77 [95% CI, 0.49-1.21]); 2-y OS rates were 47.8% vs 37.6%, respectively. Median PFS by investigator was 5.6 mo (95% CI, 3.7-7.5) with avelumab + BSC vs 2.1 mo (95% CI, 1.9-4.0) with BSC alone (HR, 0.64 [95% CI, 0.42-0.97]); 2-y PFS rates were 23.5% vs 11.3%, respectively. Long-term safety in pts with high BMI was generally consistent with the overall safety population (Table). Conclusions: This exploratory analysis shows the long-term efficacy and tolerability of avelumab 1L maintenance in pts with high BMI in JAVELIN Bladder 100, with no new safety concerns identified. These results further support the use of avelumab 1L maintenance as standard of care in pts with aUC who are progression free after 1L platinum-based chemotherapy, including pts with high BMI. Clinical trial information: NCT02603432 . [Table: see text]

Intracranial response pattern, tolerability and biomarkers associated with brain metastases in non-small cell lung cancer treated by tislelizumab plus chemotherapy.

Programmed cell death protein-1/programmed cell death protein-ligand 1 (PD-1/PD-L1) inhibitor and chemotherapy are the standard treatment for advanced non-small cell lung cancer (NSCLC) without sensitizing mutations. However, patients with untreated, symptomatic or recently-irradiated brain metastases (BMs) are mostly excluded from immunochemotherapy trials. This study aims to evaluate the intracranial response pattern, tolerability and biomarkers of tislelizumab plus chemotherapy in NSCLC with untreated, symptomatic or recently-irradiated BM. This multicenter, single-arm, phase 2 trial enrolled patients with treatment-naïve, brain-metastasized NSCLC. BM could be untreated or irradiated. Symptomatic or recently-irradiated BMs that were deemed clinically stable were allowed. Patients received tislelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (AUC =5) on day 1 every 3 weeks for 4 cycles, followed by maintenance with tislelizumab plus pemetrexed. Primary endpoint was 1-year progression-free survival (PFS) rate. Secondary endpoints included intracranial efficacy and tolerability. PD-L1 expression, tumor mutational burden (TMB) and genomic alterations were evaluated as potential biomarkers. A total of 36 patients were enrolled, 19.2% had prior brain radiotherapy, 8.3% had symptomatic BMs that required corticosteroids ≤10 mg/d or antiepileptics. Confirmed systemic and intracranial ORR (iORR) was 43.8% and 46.7%, respectively. One-year systematic PFS rate and One-year iPFS rate was 36.8% and 55.8%, respectively. About 41.7% patients had neurological adverse events, 90% patients had concordant intracranial-extracranial responses. No intracranial pseudoprogression or hyperprogression occurred. Patients with prior brain radiation trended towards higher systemic (83.3% vs. 34.6%) and iORR (75.0% vs. 42.3%). Similar intracranial efficacy was observed in tumors with different PD-L1 and TMB levels, while alterations in cytokine receptors pathway predicted higher iORR (P=0.081), prolonged systematic PFS [hazard ratio (HR) =0.16, P=0.021] and overall survival (OS) (HR =0.71, P=0.029). Untreated or irradiated BMs in NSCLC follows a conventional response and progression pattern under immunochemotherapy with altered cytokine receptors pathway being a potential biomarker for systemic and intracranial outcomes.

Relationship Between Adverse Events and Progression-free Survival in Patients Receiving Cabozantinib for Previously Treated Metastatic Renal Cell Carcinoma.

Although the adverse events (AEs) of drugs, such as sunitinib and axitinib, have been shown to predict treatment responses, evidence to support cabozantinib-induced AEs as predictors of responses to treatment for metastatic renal cell carcinoma (mRCC) is limited. Therefore, we herein investigated the relationship between AE profiles and progression-free survival (PFS) in patients receiving cabozantinib for previously treated mRCC. The present study retrospectively analyzed 40 patients receiving cabozantinib for previously treated mRCC between July 2020 and August 2022. PFS was estimated using the Kaplan-Meier method and the impact of several parameters, including cabozantinib-induced AEs, on PFS was investigated by a Cox proportional regression analysis. The median observation period was 15 (2-29) months, during which time 31 patients (77.5%) progressed, with median PFS of 11 months. Thirty-nine patients (97.5%) developed at least one AE. Liver toxicity occurred in 16 patients (40.0%) and hand-foot syndrome, hypertension, and diarrhea in 14 each (17.5%). Only hypertension correlated with longer PFS. A multivariate analysis identified hypertension as an independent prognostic factor for PFS (p=0.049). These results suggest the potential of treatment-induced hypertension as a significant predictor of prolonged PFS in patients receiving cabozantinib for mRCC.

Combining Homologous Recombination-Deficient Testing and Functional RAD51 Analysis Enhances the Prediction of Poly(ADP-Ribose) Polymerase Inhibitor Sensitivity.

To meet the urgent need for accessible homologous recombination-deficient (HRD) test options, we validated a laboratory-developed test (LDT) and a functional RAD51 assay to assess patients with ovarian cancer and predict the clinical benefit of poly(ADP-ribose) polymerase inhibitor therapy. Optimization of the LDT cutoff and validation on the basis of samples from 91 patients enrolled in the ENGOT-ov24/NSGO-AVANOVA1&2 trial (ClinicalTrials.gov identifier: NCT02354131), previously subjected to commercial CDx HRD testing (CDx). RAD51 foci analysis was performed and tumors with ≥five foci/nucleus were classified as RAD51-positive (homologous recombination-proficient). The optimal LDT cutoff is 54. Comparing CDx genome instability score and LDT HRD scores show a Spearman's correlation of rho = 0.764 (P < .0001). Cross-tabulation analysis shows that the sensitivity of the LDT HRD score is 86% and of the LDT HRD status is 91.8% (Fisher's exact test P < .001). Survival analysis on progression-free survival (PFS) of LDT-assessed patients show a Cox regression P < .05. RAD51 assays show a correlation between low RAD51 foci detection (<20% RAD51+ cells) and significantly prolonged PFS (P < .001). The robust concordance between the open standard LDT and the CDx, especially the correlation with PFS, warrants future validation and implementation of the open standard LDT for HRD testing in diagnostic settings.

T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.

Sorafenib plus transarterial chemoembolization vs sorafenib alone for patients with advanced hepatocellular carcinoma: A systematic review and meta-analysis.

Although the past decade has seen remarkable advances in treatment options for hepatocellular carcinoma (HCC), the dismal overall prognosis still envelops HCC patients. Several comparative trials have been conducted to study whether transarterial chemoembolization (TACE) could improve clinical outcomes in patients receiving sorafenib for advanced HCC; however, the findings have been inconsistent. To study the potential synergies and safety of sorafenib plus TACE vs sorafenib alone for treating advanced HCC, by performing a systematic review and meta-analysis. This study was conducted following the PRISMA statement. A systematic literature search was conducted using the Cochrane Library, Embase, PubMed, and Web of Science databases. Data included in the present work were collected from patients diagnosed with advanced HCC receiving sorafenib plus TACE or sorafenib alone. Data synthesis and meta-analysis were conducted using Review Manager software. The present study included 2780 patients from five comparative clinical trials (1 was randomized control trial and 4 were retrospective studies). It was found that patients receiving sorafenib plus TACE had better prognoses in terms of overall survival (OS), with a combined hazard ratio (HR) of 0.65 [95% confidence interval (95%CI): 0.46-0.93, P = 0.02, n = 2780]. Consistently, progression free survival (PFS) and time to progression (TTP) differed significantly between the sorafenib plus TACE arm and sorafenib arm (PFS: HR = 0.62, 95%CI: 0.40-0.96, P = 0.03, n = 443; TTP: HR = 0.73, 95%CI: 0.64-0.83, P < 0.00001, n = 2451). Disease control rate (DCR) was also significantly increased by combination therapy (risk ratio = 1.36, 95%CI: 1.02-1.81, P = 0.04, n = 641). Regarding safety, the incidence of any adverse event (AE) was increased due to the addition of TACE; however, no significant difference was found in grade ≥ 3 AEs. The combination of sorafenib with TACE has superior efficacy to sorafenib monotherapy, as evidenced by prolonged OS, PFS, and TTP, as well as increased DCR. Additional high-quality trials are essential to further validate the clinical benefit of this combination in the treatment of advanced HCC.

Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Prognostic nomogram model for selecting between transarterial chemoembolization plus lenvatinib, with and without PD-1 inhibitor in unresectable hepatocellular carcinoma.

To establish and verify a prognostic nomogram model for selecting in unresectable hepatocellular carcinoma (uHCC) treated by transarterial chemoembolization plus lenvatinib (TACE-L) with or without PD-1 inhibitor. Data of 241 uHCC patients who underwent TACE-L (n = 128) and TACE-L plus PD-1 inhibitor (TACE-L-P, n = 113) were retrospectively reviewed. The differences in tumour responses, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) between two groups were compared, and a prognostic nomogram model was established based on independent clinical-radiologic factors and confirmed by Cox regression analysis for predicting PFS and OS. The treatment selection for uHCC patients was stratified by the nomogram score. Compared to TACE-L, TACE-L-P presented prolonged PFS (14.0 vs. 9.0 months, P < .001), longer OS (24.0 vs. 15.0 months, P < .001), and a better overall objective response rate (54.0% vs. 32.8%, P = .001). There was no significant difference between the rate of AEs in the TACE-L-P and the TACE-L (56.64% vs. 46.09%, P = .102) and the rate of grade ≥ 3 AEs (11.50% vs. 9.38%, P = .588), respectively. The nomogram model presented good discrimination, with a C-index of 0.790 for predicting PFS and 0.749 for predicting OS. Patients who underwent TACE-L and obtained a nomogram score >9 demonstrated improved 2-year PFS when transferred to TACE-L-P, and those with a nomogram ≤25 had better 2-year OS when transferred to TACE-L-P. TACE-L-P showed significant improvements in efficiency and safety for uHCC patients compared with TACE-L. The nomogram was useful for stratifying treatment decisions and selecting a suitable population for uHCC patients. Prognostic nomogram model is of great value in predicting individualized survival benefits for uHCC patients after TACE-L or/and TACE-L-P. And the nomogram was helpful for selection between TACE-L-P and TACE-L among uHCC patients.

Clinical impact on treatment effectiveness of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

479 Background: Immune checkpoint inhibitors (ICIs) have emerged as the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, their administration poses the risk of immune-related adverse events (irAEs). Recent data suggests that the occurrence of irAEs may be associated with a favorable prognosis. Nevertheless, limited studies have explored the relationship between irAE severity or specific symptoms and clinical outcomes. Therefore, the objective of this study was to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable HCC treated with immune checkpoint inhibitors. Methods: We enrolled 130 patients with unresectable HCC treated with atezolizumab plus bevacizumab between November 2022 and January 2023 at a single center. We investigated the relationship between irAEs and both response rate and post-treatment outcomes. Results: Out of the 130 patients, 36 (27.7%) developed irAEs. Patients with irAEs exhibited a significantly longer progression-free survival (PFS) compared to the non-irAE group, with a median PFS of 8.9 months compared to 4.6 months (p &lt; 0.01). There was no difference in overall survival with or without irAEs. The irAE group demonstrated significantly higher disease control rate (DCR) compared to the non-irAE group (97.0% vs 65.5%, p &lt; 0.01). The analysis by the severity of irAE revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 months vs 4.6 months, p =0.007) and higher DCR (100% vs 65.5%, p &lt; 0.01) compared to the non-irAE group. Furthermore, hypothyroidism was correlated with a favorable PFS (8.9 months vs 5.4 months, p = 0.02), DCR (100% vs 71.3%, p = 0.03) and overall response rate (58.3% vs 18.5%, p = 0.005). Conclusions: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (Grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.

First report of the randomized phase III study of bi-weekly trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) vs. FTD/TPI monotherapy for chemorefractory metastatic colorectal cancer (mCRC): JCOG2014 (ROBiTS).

118 Background: FTD/TPI has been widely used as one of the standard therapies in the late-line treatment for patients with mCRC, and the efficacy of FTD/TPI plus BEV combination was also recently reported in the SUNLIGHT trial. However, the combination of FTD/TPI plus BEV increased the frequency of hematologic toxicity. On the other hand, several phase II studies suggested that modifying the FTD/TPI schedule in combination with BEV from 4-week intervals (2 weeks-on, 2 weeks-off) to bi-weekly dosing (1 week-on, 1 week-off) reduced hematologic toxicities without reducing efficacy. Therefore, we commenced a phase III study to confirm the superiority of bi-weekly FTD/TPI plus BEV to 4-week intervals FTD/TPI monotherapy. Methods: This study is an open-label, multicenter, phase III trial conducted in Colorectal Cancer Study Group of Japan Clinical Oncology Group. We randomly assigned, in a 1:1 ratio, patients who were refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, angiogenesis inhibitor, anti-EGFR antibody (if RAS-wild type), BRAF inhibitor and anti-EGFR antibody (if BRAF V600E-mutant), and immune check point inhibitor (if dMMR/MSI-H) to the treatment of mCRC to receive 4-week intervals FTD/TPI 70mg/m2/day monotherapy (arm A) or bi-weekly FTD/TPI plus bevacizumab 5mg/kg (arm B). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety. Results: In consideration of the results of the SUNLIGHT trial, this study was prematurely terminated. Between January 2022 and February 2023, a total of 152 patients were randomized (75 in the arm A and 77 in the arm B). Patient backgrounds between the two arms were well balanced. At the data cut-off date, all enrolled patients discontinued protocol treatment due to disease progression (69.3% vs. 59.7%) and treatment-related adverse events (6.7% vs. 2.6%). With a median follow-up of 8.3 months for surviving patients (OS events, 45% vs. 40%), the median OS was 12.2 vs. 11.8 months (hazard ratio [HR], 0.905; 95% confidence interval [CI], 0.556 to 1.473) and the median PFS was 2.4 vs. 4.0 months (HR, 0.607; 95% CI, 0.426 to 0.865). RR was 1.3% vs. 5.3% and DCR was 45.3% vs. 53.3%. The most common Grade 3 or higher adverse events in each group were neutropenia (46.6% vs. 24.0%), anemia (15.1% vs. 4.0%), fatigue (2.7% vs. 8.0%), anorexia (5.5% vs. 5.3%), nausea (5.5% vs. 5.3%) and febrile neutropenia (4.1% vs. 0%). Conclusions: Although this study was terminated early, the bi-weekly FTD/TPI plus BEV combination in late-line chemotherapy for patients with mCRC resulted in prolonged PFS and reduced hematologic toxicity compared to 4-week intervals FTD/TPI monotherapy. Long-term results including OS are currently under follow-up. Clinical trial information: jRCTs031210544 .

Clinical outcomes and medical resource utilization of toripalimab combination therapy versus bevacizumab plus chemotherapy in advanced non-squamous non-small cell lung cancer

Objective This study aimed to evaluate the real-world clinical efficacy and safety, economic burdens and medical resource utilization (MRU) of toripalimab treatment patterns compared with bevacizumab plus chemotherapy (BCP) for patients with advanced non-squamous NSCLC in China. Methods Progression-free survival (PFS), adverse drug reactions (ADR) and the costs of drugs, laboratory testing, imageology examinations (including CT, B ultrasound, MRI), medical service, nursing, treatment, genetic test and medical disposable material were compared between two groups. A retrospective observational study was conducted with electronic medical records from Fudan University Huashan hospital. Data was obtained from established electronic medical records (EMRs) and patient surveys. Survival time from the study enrollment to disease progression or death plus from 1st progression disease (PD) in the maintenance phase to 2nd PD (PFS II), adverse events (AE), direct medical costs, MRU and AE-related costs were collected and compared between toripalimab group and BCP group. A total of 246 patients were enrolled. Results Toripalimab combination therapy has significantly prolonged PFS comparing with BCP (13.8 months vs. 6.2 months, p < .001). A statistically significant improvement in PFS was observed favoring all toripalimab regimen subgroups compared with the bevacizumab group. Patients in toripalimab group occupied more overall resource consumption, more direct medical costs ($47,056.9 vs. $29,951.0, p < .0001) and AE-related costs ($4,500.2 vs. $784.4, p < .0001) than BCP group. Although patients in the toripalimab group used more drugs to prevent AEs ($4,500.2 vs. $784.4, p < .0001), they still experienced more AEs than patients in BCP group (51.4% vs. 41.4%). Conclusion Toripalimab combination therapy could significantly prolonged PFS for patients with advanced non-squamous NSCLC compared with BCP, but at the expense of more MRU, costs and AEs.

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study.

LBA588 Background: Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor. Methods: Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS. Results: Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p &lt; 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p &lt; 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm). Conclusion: 177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488 .

Pharmacogenomic study of gemcitabine on the safety and efficacy in patients with metastatic pancreatic cancer (GENESECT study): Analysis of a subpopulation.

651 Background: In the GENESECT study, we examined the relationships between gemcitabine (GEM) metabolism-related germline genetic polymorphisms (GPs) and treatment efficacy and safety. However, no significant GPs were found because approximately 70% of the patients were treated with nab-paclitaxel, which has a different metabolic process than GEM. In the present study, a subanalysis including only GEM monotherapy patients was performed. Methods: Of the 159 patients analyzed in the GENESECT study, only the GEM monotherapy patients were selected. The endpoints were the carbohydrate antigen 19-9 (CA19-9) response (reduction ≥50% from the pretreatment level at 8 weeks), progression-free survival (PFS), and overall survival (OS) in relation to GPs from the viewpoint of efficacy, and neutropenia ≥Grade 3 and thrombocytopenia ≥Grade 3 in relation to GPs from the viewpoint of safety. The analyzed genes included those encoding GEM transporters and metabolic enzymes ( SLC29A1, ABCC5, CDA, DCK, RRM1/2), and a tumor cell proliferation enzyme ( COX-2). Statistical analysis included univariate and multivariate logistic regression analyses. The significance level was set to 5%. Results: Data of 50 patients were analyzed. AA genotype in ABCC5 1146A&gt;G (rs7636910) was associated with a significantly higher percentage of CA19-9 responses compared to AG/GG (52.9% vs 21.2%, p = 0.023), and the association remained significant on multivariate analysis (OR: 6.255, p = 0.014). Patients with AA genotype in ABCC5 1146A&gt;G tended to be associated with PFS, but this was not statistically significant (HR: 0.464, p = 0.074). On the other hand, there was no significant association between CA19-9 responses and DCK-1205C&gt;T (rs4694362), TT/CT genotype in DCK-1205C&gt;T was significantly associated with prolonged PFS compared to CC (median, 127 vs 48 days, p = 0.002), and the association remained significant on multivariate analysis (HR: 0.153, p = 0.028). No GPs were significantly associated with OS, and the presence of second-line chemotherapy was the only relevant factor. In terms of safety, no GPs were significantly associated with either neutropenia or thrombocytopenia. Conclusions: The results suggest that ABCC5 and DCK might be related to the efficacy of treatment with GEM, but further research is needed. Clinical trial information: UMIN000012720 .

The impact of social vulnerability index on survival following autologous stem cell transplant for multiple myeloma

Autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for eligible patients with multiple myeloma (MM) to prolong progression-free survival (PFS). While several factors affect survival following ASCT, the impact of social determinants of health such as the CDC Social Vulnerability Index (SVI) is not well documented. This single-center retrospective analysis evaluated the impact of SVI on PFS following ASCT in MM patients. 225 patients with MM who underwent ASCT participated, with 51% transplanted in the last 5 years. At 5 years post-transplant, 55 (50%) achieved PFS and 66 (60%) remained alive. Higher SVI values were significantly associated with lower odds of PFS (OR = 0.521, p < 0.01, 95% CI [0.41, 0.66]) and OS (OR = 0.592, p < 0.01, 95% CI [0.46, 0.76]) post-transplant. Greater vulnerability scores in the socioeconomic status (OR = 0.890; 95% CI: [0.82, 0.96]), household characteristics (OR = 0.912; 95% CI: [0.87, 0.95]), and racial and ethnic minority status (OR = 0.854; 95% CI: [0.81, 0.90]) themes significantly worsened the odds of PFS. These results suggest high SVI areas may need more resources to achieve optimal PFS and OS. Future studies will focus on addressing factors within the socioeconomic status, household characteristics, and racial and ethnic minority subthemes, as these have a more pronounced effect on PFS.