Failure Of First-line Therapy Research Articles

Clinical evaluation of sintilimab in conjunction with bevacizumab for advanced colorectal cancer with microsatellite stable-type after failure of first-line therapy

Clinical evaluation of sintilimab in conjunction with bevacizumab for advanced colorectal cancer with microsatellite stable-type after failure of first-line therapy

Thrombopoietin Receptor Agonists as Second-Line Treatment in Children With Ongoing Immune Thrombocytopenia

What Is the Issue? Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelets and an increase in bleeding risk; in the pediatric population, the reported incidence rate varies between 2 and 5 per 100,000 children per year. Spontaneous remission may be observed in up to 70% of patients, while 20% of patients may experience severe bleeding symptoms. In children whose ITP does not respond to first-line corticosteroids, IV immunoglobulin (IVIG), or anti-D immunoglobulin, guidelines recommend the use of thrombopoietin receptor agonists (TPO-RAs), i.e., eltrombopag or romiplostim (avatrombopag did not have a marketing authorization and Notice of Compliance at the time that the review was initiated). Rituximab is considered a subsequent-line of therapy. Splenectomy is not usually considered an appropriate treatment option in children. The goal of therapy in pediatric patients with ITP is to reduce bleeding and improve quality of life. Platelet response is considered a valid and appropriate surrogate end point in studies and routine assessment in clinical practice. Children whose ITP does not respond to available first-line drugs may require subsequent treatment with off-label drugs because they do not have access to TPO-RAs. What Did We Do? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence. A systematic review of the literature identified 5 studies (4 randomized controlled trials [RCTs] and 1 observational study), which were synthesized narratively. The review addressed the following policy questions: In children with ongoing, active ITP, what is the overall body of evidence supporting the use of TPO-RAs and rituximab after failure of first-line therapies? Based on the level and quality of clinical evidence, should TPO-RAs be reimbursed for use earlier in the treatment sequencing for children with ongoing, active ITP, instead of being reimbursed only after a course of rituximab? What Did We Find? Evidence from 2 RCTs (n = 159) suggests that eltrombopag likely increases and maintains platelet response over time, in addition to decreasing the use of rescue medication and clinically significant bleeding compared to placebo, which were considered clinically meaningful outcomes for pediatric patients with ITP. There was a low risk of bias in the studies, but uncertainty was introduced due to the small sample sizes. Evidence from 1 RCT (n = 62) suggests that romiplostim may also increase and maintain platelet response, as well as reduce clinically significant bleeding compared to placebo. However, there was some concern due to a high risk of bias in the studies and uncertainty due to the small sample size, which suggests a need for caution in the interpretation of the findings. The effectiveness of rituximab was inconclusive due to the lack of evidence, as no comparative RCTs could be identified, while the observational study included presented only descriptive comparisons. No evidence was identified in support of trying rituximab before accessing TPO-RAs. What Does This Mean? Given that ITP is rare in children, there is a gap in available relevant evidence, and robust evidence from large RCTs in this patient population are unlikely to be conducted. Jurisdictions may consider requesting an implementation advice panel for use of eltrombopag and romiplostim after failure of first-line therapies in children with ongoing, active ITP.

Beyond HMAs: Novel Targets and Therapeutic Approaches

Myelodysplastic syndromes/neoplasms (MDS) constitute a heterogeneous group of clonal hematopoietic disorders with extremely variable clinical features and outcomes. Management of MDS is largely based on risk stratification of patients into either lower-risk or higher-risk categories using the International Prognostic Scoring System-Revised and, more recently, on the Molecular International Prognostic Scoring System. Lower-risk MDS is often managed with the goal of ameliorating cytopenias and improving quality of life, while higher-risk MDS is treated with therapies aimed at extending survival and delaying progression to acute myeloid leukemia (AML). Therapeutic strategies in lower-risk MDS patients may consist of erythropoiesis stimulating agents, luspatercept, and lenalidomide for selected patients. Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS. In higher-risk MDS, monotherapy with hypomethylating agents continues to be the standard of care. While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy. Moreover, biomarker-directed therapies as well as immonotherapeutic approaches are currently being evaluated in early phase trials. Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms.

Biologics or Janus Kinase Inhibitors in Rheumatoid Arthritis Patients Who are Insufficient Responders to Conventional Anti-Rheumatic Drugs.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis.

NURS-01. NOVEL TREATMENTS FOR ACNEIFORM ERUPTIONS CAUSED BY TARGETED THERAPIES IN THE PEDIATRIC POPULATION

Abstract BACKGROUND Drugs that target the mitogen-activated protein kinase pathway can cause frequent and severe cutaneous toxicities with acneiform eruptions being one of the most common and challenging to manage. The literature is limited regarding treatment recommendations especially when this rash is refractory to first-line therapies. METHODS A single-institution case series regarding the treatment of acneiform eruptions with oral isotretinoin after failure of first-line therapies was performed. RESULTS Two female, adolescent patients who developed refractory acneiform eruptions while on trametinib were included. Their acneiform eruption emerged within the first cycle of trametinib requiring treatment with oral doxycycline plus a variety of topical medications. They remained on doxycycline for 6 and 7 months. Both patients then switched to oral isotretinoin after minimal rash response and rebound of the rash when attempting to discontinue doxycycline. The initial isotretinoin doses were 0.2-0.3 mg/kg/day rounded per pill size. Both patients required a dose reduction due to worsening xerosis. Once decreased, isotretinoin was well tolerated. No changes in baseline lipid panels or ALT were seen. No associated neurologic symptoms or pseudotumor cerebri. While on oral isotretinoin, no additional topical therapies were required to treat the acneiform eruption. The first patient’s acneiform rash improved from a CTCAE v5 grade 3 to grade 1 after only 3 weeks of isotretinoin. All locations of the rash responded to therapy. The second patient developed a grade 2 acneiform rash after starting trametinib and became ungradable with only residual pink papules to cheeks after receiving isotretinoin. CONCLUSIONS Both patients were successfully treated with isotretinoin after multiple prior therapies including 6 or more months of treatment with oral antibiotics. We recommend further research of treatment therapies in addition to oral antibiotics given concerns on their impact of the microbiome.

Clinical features, cerebrospinal fluid changes, and prognosis in Chinese patients with autoimmune encephalitis.

Autoimmune encephalitis (AE) is a rare, treatable disease of the central nervous system (CNS) caused by an antibody-related immune response. This study is to investigate the correlation of clinical features, cerebrospinal fluid (CSF) characteristics, and prognosis in patients with AE. A total of 71 patients diagnosed with antibody-positive AE were retrospectively analyzed. The patients were divided into three groups: anti-NMDAR group, anti-LGI1 group, and other types. Clinical data were collected to analyze clinical features and CSF results, and prognosis was determined by modified Rankin Scale (mRS). There was statistical difference in the incidences of decreased consciousness level (P < 0.001), memory loss (P = 0.017), speech disorders (P = 0.035), and dyskinesia (P = 0.001) in different antibodies groups. Younger age (P = 0.018), elevated CSF chloride content (P = 0.006), and white blood cells > 50/mm3 (P = 0.026) were highly correlated with ICU admission. Anti-LGI1 encephalitis had a relatively small risk for ICU admission (P = 0.034), and a lower risk of poor functional recovery (P = 0.048) and recurrence (P = 0.041). Patients with first-line treatment failure (P = 0.021) had an increased risk of poor functional recovery. Delayed treatment (P = 0.011) would increase the risk of recurrence. There are differences in age, gender, clinical characteristics, and CSF results in different subtypes of AE. First-line therapy failure would have poor functional recovery, and delayed therapy would increase the risk of relapse. Chloride ion content and white blood cell count in cerebrospinal fluid are positively correlated with the patient's exacerbation and admission to ICU. These indicators have certain clinical value for the prognosis of AE patients.

Survival impact of sequential chemotherapy following pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma.

Pembrolizumab alone or combined with chemotherapy is the standard of care for first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with positive programmed death-ligand 1 combined positive scores. However, data on second-line chemotherapy following pembrolizumab are scarce. A single-center, retrospective study was conducted to determine the efficacies of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatments and the efficacy of second-line chemotherapy for patients with R/M HNSCC who were refractory or intolerant to first-line treatment. Fifty-four patients were treated with pembrolizumab, and 29 received second-line therapy, with 27 opting for cetuximab-containing regimens. The median progression-free survival (PFS), overall survival (OS), and PFS on next-line therapy for first-line treatment were 4.7 (95% confidence interval [CI], 2.1-8.7), 22.1 (95% CI, 12.6-not reached), and 15.6months (95% CI, 9.7-not reached) in the pembrolizumab group and 5.4 (95% CI, 3.3-6.8), 15.8 (95% CI, 8.6-not reached), and 13.7months (95% CI, 8.1-not reached) in the pembrolizumab plus chemotherapy group, respectively. The overall response rate and median PFS for second-line treatment were 48.3% (95% CI, 30.4-67.0) and 6.1months (95% CI, 2.30-8.84). The median OS for patients who received second-line treatment was 18.4months, which was superior to the median OS of 6.0months for patients who received the best supportive care (log-rank p = 0.10). This study indicates that cetuximab-containing second-line chemotherapy can improve outcomes in R/M HNSCC, even after first-line therapy failure or intolerance.

An Advanced Intrahepatic Cholangiocarcinoma Patient Benefits from Personalized Immunotherapy.

Advanced intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by limited response to standard therapeutic modalities, such as radiotherapy, chemotherapy, and targeted therapy. The prognosis for patients with advanced ICC is exceedingly bleak, with an overall survival of less than 1 year. In recent years, personalized neoantigen vaccines have emerged as a promising approach to augment the immune response against tumors. Clinical investigations are currently underway to evaluate the efficacy of neoantigen-based peptide, DNA, and dendritic cell vaccines. Herein, we present a noteworthy case of advanced ICC patients who experienced disease progression following relapse and subsequently received immunotherapy with a personalized neoantigen nanovaccine. This innovative treatment strategy involved the administration of a custom-designed neoantigen-based peptide nanovaccine tailored to the patient's specific gene mutation profile subsequent to failure of first-line therapy. The clinical efficacy and anti-tumor immune responses were evaluated using various methods, including imaging, interferon-γ ELISPOT assay, and intracellular cytokine staining. Notably, the neoantigen nanovaccine elicited a robust and specific tumor-killing effect mediated by T cells, resulting in a durable response lasting up to 25 months. These findings highlight the potential of neoantigen-based immunotherapy as a novel therapeutic avenue for the management of advanced ICC.

P634 Durability of a second-line anti-TNFɑ agent compared to a different mechanism of action after first anti-TNFɑ failure in ulcerative colitis: CambiaCU Study

Abstract Background After first anti-TNFɑ (aTNF) failure in ulcerative colitis (UC), switching to a different mechanism of action (MoA) could decrease the rates of failure and discontinuation compared to a second aTNF and with a better safety profile. Methods We performed a multicenter and retrospective study (6 Andalusian sites) in which patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA such as ustekinumab (UST), vedolizumab (VDZ), tofacitinib and filgobinib (JAK) were included. The aim of our study was to evaluate the long-term durability of a different MoA compared to a second aTNF after a first-line therapy failure with aTNF. Results 185 patients with UC were included. There were no significant differences between both groups in term of age, sex, extension of disease, extraintestinal manifestations or IMIDs, smoking habit or HLA-DQA1*05. The only significant difference was disease duration (9 years MoA vs 12 years in second aTNF, p=0.02). 80 patients received a different MoA (37 VDZ, 24 UST, 7 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). Duration of first aTNF, although non-significant (p=0.06), tended to be shorter in the MoA group (7 months vs 12 months in aTNF group). The most frequent cause of suspension of first aTNF in the MoA group was primary failure (46% vs 31%, p= 0.02) and in the second aTNF group was secondary failure (51% vs 35%, p=0.02). The follow-up mean was 22.4 months in the group of a different MoA and 23.3 months in the second aTNF group. 60% of patients discontinued the second-line biological treatment, 64% with aTNF vs 35% with a different MoA. Durability of therapies in the group of different MoA was significatively longer compared with second aTNF (50% vs 31.4%, p=0.036) (figure 1). JAK showed the best durability (63.2%), followed by UST (66.7%), IFX (52.9%), VDZ (32.4%), ADA (21.7%) and golimumab (18.2%), with significant differences (p=0.03). Reasons for discontinuation were primary failure in 29.7% (63.6% second aTNF vs 36.4% different MoA), secondary failure in 25.9% (64.5% second aTNF vs 35.5% different MoA) and intolerance or adverse events in 6.4% (66.6% second aTNF vs 34.4% different MoA). Adverse events were reported in 12 patients, 8 with aTNF a 4 with other MoA (2 vs 0 infusion reactions, 1 vs 1 mild infections, 2 vs 1 respiratory adverse effects, 1 vs 1 cutaneous reactions, 1 vs 0 musculoskeletal effects, 1 vs 1 neoplasia). Conclusion Our study shows that after a first aTNF failure in UC, a switch to a biological therapy with a different MoA achieves longer survival compared to switching to a second aTNF, with less primary and secondary failure.

Efficacy of transarterial chemoembolization with drug-eluting beads combined with systemic chemotherapy and targeted therapy in colorectal cancer liver metastasis

BackgroundSystemic therapy is the standard treatment for unresectable colorectal cancer with liver metastasis (CRCLM). Transarterial chemoembolization with drug-eluting beads (DEB-TACE) is considered an effective treatment option for CRCLM. Few studies have investigated the combination of DEB-TACE, chemotherapy, and targeted therapy for CRCLM. In the present study, we evaluated the disease control rate (DCR), adverse events, and survival among patients with CRCLM who underwent the combination of DEB-TACE and chemotherapy/targeted therapy.MaterialsWe retrospectively reviewed 35 patients with CRCLM who were treated between January 2015 and January 2021. Standard systemic chemotherapy, targeted therapy, and 66 DEB-TACE procedures were administered. Data were collected on each DEB-TACE procedure, including chemotherapy agents, tumor burden of liver metastasis, number of DEB-TACE courses, and adverse events. Patients who received DEB-TACE after failure of first-line systemic therapy were categorized into the first-line failure group. Patients who received DEB-TACE after the failure of second-line, third-line, or fourth-line therapy were categorized into the other group. Subgroup analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between the two groups.ResultsIn total, 35 patients with CRCLM (34 patients with adenocarcinoma and 1 patient with neuroendocrine carcinoma) were enrolled. In total, 13 patients (37.1%) had extrahepatic metastases at initial diagnosis. In this study, 66 DEB-TACE procedures were performed. The DCR was 54.3%. The median OS period was 47.4 months, and the estimated 3-year OS rate was 59.5%. The median PFS period was 6.3 months, and the estimated 1-year PFS rate was 20.6%. The PFS period was longer in the first-line failure group than in the other group (7.2 vs. 6.3 months). No significant difference was observed in OS between the two groups. Four episodes (6.1%) of grade 3 intra-abdominal infection were observed.ConclusionThe combination of chemotherapy, targeted therapy, and DEB-TACE can lead to a favorable DCR and survival outcomes in patients with CRCLM. Early intervention with DEB-TACE (i.e., after the failure of first-line therapy) has the potential to extend the PFS period in patients with CRCLM. Severe adverse events were rare and manageable. Further prospective, randomized controlled studies are warranted to obtain more conclusive findings.

Beyond the horizon: emerging therapeutic approaches in myelodysplastic neoplasms

Management of myelodysplastic neoplasms (MDS) requires a personalized approach, with a focus on improving quality of life and extending lifespan. The International Prognostic Scoring System-Revised and the molecular International Prognostic Scoring System are key tools for risk stratification and management of MDS. They provide a framework for predicting survival and the risk of transformation to acute myeloid leukemia. However, a major challenge in MDS management remains the limited therapeutic options available, especially after the failure of first-line therapies. In lower-risk MDS, the failure of erythropoietin-stimulating agents often leaves few alternatives, although in higher-risk MDS, the prognosis after hypomethylating agent failure is dismal. This highlights the urgent need for novel, more personalized therapeutic approaches. In this review, we discuss emerging novel therapeutic approaches in the treatment of MDS. Several new therapeutic targets are currently being evaluated, offering hope for improved management of MDS in the future.

Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling.

Traditional prognostic models for newly diagnosed patients with multiple myeloma (MM), including International Staging System criteria and number of high-risk chromosomal abnormalities, are based on disease characteristics at diagnosis. However, the identification of patients at risk of more rapidly progressive MM is inherently a dynamic assessment. In a subset of patients with MM, adverse disease biology only becomes evident after the failure of first-line therapy. We define this entity as functional high-risk MM (FHRMM), encompassing relapse within 18 months of treatment initiation and/or within 12 months of frontline autologous stem cell transplantation. FHRMM is not adequately captured by traditional prognostic models, and there is a need for better understanding of mechanisms or risk factors for early relapse or progression. In this review, we explore potential definitions of FHRMM before delving into its underlying drivers based on genetic, transcriptomic, and immune cell profiling studies. Emerging data suggest that specific features of both myeloma cells and immune cells can enable the FHRMM phenotype. We conclude our review by discussing ongoing and future studies that seek to identify and intervene upon patients with FHRMM preemptively.

105P A phase II study of SHR-1316 plus IBI310 in patients with advanced intrahepatic cholangiocarcinoma after failure of first-line therapy

105P A phase II study of SHR-1316 plus IBI310 in patients with advanced intrahepatic cholangiocarcinoma after failure of first-line therapy

Treatment of Adult Patients With Chronic Immune Thrombocytopenia After Failure of First-Line Therapies

Treatment of Adult Patients With Chronic Immune Thrombocytopenia After Failure of First-Line Therapies

A cost-utility analysis of thrombopoietin receptor agonists for treating pediatric immune thrombocytopenia purpura after failure of first-line therapies.

Thrombopoietin receptor agonists (TPO-RAs) have emerged as a recommended treatment for children with persistent and/or chronic immune thrombocytopenic purpura (ITP). The purpose of this study was to evaluate the cost-effectiveness of TPO-RAs relative to treatment without TPO-RAs (non-TPO-RAs/usual care) for ITP in children who do not respond to first-line therapy and in whom splenectomy is not recommended in Ontario, Canada, from a hospital payer perspective. A 2-year Markov model with an embedded decision tree was used. Data on medications used, dose, response rate, bleeding, and emergency treatment events were collected from the Hospital for Sick Children in Toronto. The health outcomes were described in quality-adjusted life-years (QALYs). Health-state utilities were derived from the peer-reviewed literature. Scenario analyses, deterministic, and probabilistic sensitivity analyses were conducted. Economic costs were measured in 2021 Canadian dollars ($1.00=US$0.80) RESULTS: TPO-RAs are estimated to result in an increased cost of $27,118 and a QALY gain of 0.21 compared to non-TPO-RAs over a 2-year horizon, resulting in an incremental cost-effectiveness ratio (ICER) of $129,133. In a 5-year scenario analysis, the ICER fell to $76,403. In the probabilistic sensitivity analysis, TPO-RAs exhibit a 40.0% probability of being cost-effective at a conventional ($100,000) willingness-to-pay threshold per QALY gained. Further assessment of the long-term efficacy of TPO-RAs is warranted to obtain more precise long-term estimates. As the costs of TPO-RAs decline with the introduction of generic formulations, TPO-RAs may be increasingly cost-effective.

A real-world study of TACE combined with regorafenib as a second-line treatment for advanced hepatocellular carcinoma.

e16144 Background: Regorafenib is a guideline-recommended second-line systemic drug, and its combination with transarterial chemoembolization (TACE) for the treatment of advanced liver cancer after first-line therapy has been gradually recognized by clinicians. We investigated the efficacy and safety of TACE combined with regorafenib with or without anti-PD-1 immunotherapy as a second line choice for advanced hepatocellular carcinoma (HCC). Methods: In this retrospective study, we retrieved patients with advanced liver cancer who had failed first-line therapy in our center from January 2019 to December 2021, and screened out patients who received TACE combined with regorafenib as second-line therapy. The data of objective response rate (ORR), progression-free survival (PFS) and adverse reactions (ARs) of treatment in these patients were analyzed and summarized. Subgroup analysis of patients with and without PD-1 inhibitors was also performed. Results: A total of 43 eligible patients were screened and treated with TACE in combination with regorafenib in second-line therapy, including 29 patients treated with PD-1 inhibitors. In all patients, one patient had complete response (CR) and 11 patients had partial response (PR), with ORR of 27.91% (12/43) and 24 patients had stable disease (SD), with disease control rate (DCR) of 83.72% (36/43). The median PFS was 10.0 months for all patients in survival follow-up, with PFS rates of 77.65% and 37.17% at 6 and 12 months follow-ups, respectively. Overall survival (OS) rates were 90.49%, 67.03%, and 58.65% at 12, 18, and 24 months, respectively. In subgroup analysis, there was no statistical difference in median PFS between the groups with or without PD-1 inhibitors (11.0 months vs 8.0 months, p=0.229), but there was a trend toward survival benefit in the combined group (hazard ratio/HR 0.62). The incidence of treatment-related ARs in all treated patients was 81.40% (35/43), all grade 1-2. Among ARs, hand-foot syndrome (27.91%), loss of appetite (20.93%), and elevated transaminases (16.28%) were predominant. Conclusions: This study verified the efficacy and safety of TACE combined with regorafenib as second-line therapy for the treatment of advanced HCC after failure of first-line therapy, and the results need to be further justified in future prospective studies with larger sample sizes. [Table: see text]

Efficacy and safety of regorafenib alone or in combinations in the second-line setting for advanced hepatocellular carcinoma: A multicenter real-world study.

e16172 Background: Due to drug resistance or intolerable adverse events, most hepatocellular carcinoma (HCC) patients tend to experience TKI-based first-line therapy failure. However, there is no unified choice of second-line treatment after this. Different authors have demonstrated that the combination of regorafenib and PD-1 inhibitors or TACE depicts synergistic effect. Therefore, the major goal of this research is to explore the efficacy and safety of regorafenib alone or in combinations as second-line therapy for advanced HCC in a real-world setting. Methods: In this study 94 advanced HCC patients (84 male and 10 females, average age of 59.8 years) were included from 3 Chinese centers between September 2018 and August 2022. It includes pathologically or clinically diagnosed advanced HCC patients who received regorafenib alone or in combinations in the second-line setting for at least 28 consecutive days. The primary endpoints were objective response rate (ORR, mRECIST criteria), and progression-free survival (PFS), however, the secondary endpoints included overall survival (OS) rate at 12-month, disease control rate (DCR) and treatment-related adverse events (TRAEs). Statistical analysis was performed with Kaplan-Meier method by using log-rank test. Results: 32 (34.0%) patients had BCLC stage B (others had BCLC stage C) and 72 (76.6%) patients were of Child-Pugh A (others were of Child-Pugh B). Half of the patients received regorafenib 160mg once daily during weeks 1–3 of each 4-week cycle. The proportions of patients received single drug regorafenib therapy (REGO) and combination therapies (COM) were 26.6% and 73.4%, respectively. The combination treatment regimens included regorafenib plus PD-1 inhibitors (36.2%), regorafenib combined with TACE (11.7%), and triple therapy (regorafenib, PD-1 inhibitors, TACE) (25.5%). The ORR and DCR were 28.7% and 72.3% with a median PFS of 8.4 months (range 6.33-10.47) and 12-month OS rate was 92.6%. The median PFS of COM group was 8.7 months ranging from 7.09-10.32, which was significantly longer compared to REGO group (4.2 months, range 0.45-7.95) (P = 0.031). Moreover, 66 (70.2%) recipients had TRAEs and most frequent TEAEs (≥5%) included hand-foot syndrome (31.9%), diarrhea (20.2%), rash (13.8%), fatigue (7.4%), oral mucositis (7.4%) and arthralgia (5.3%). 12 (12.8%) recipients had grade 3 TRAEs, including hand-foot syndrome (8.5%), hypertension (2.1%), diarrhea (1.1%) and rash (1.1%). No Grade 4 TRAE and new safety signal were identified. Conclusions: In the second-line treatment of advanced HCC, regorafenib alone or in combinations is effective and well-tolerated. The combination therapy showed a longer survival than regorafenib alone.

Could Inhibiting the DNA Damage Repair Checkpoint Rescue Immune-Checkpoint-Inhibitor-Resistant Endometrial Cancer?

Endometrial cancer (EC) is increasingly undermining female health worldwide, with poor survival rates for advanced or recurrent/metastatic diseases. The application of immune checkpoint inhibitors (ICIs) has opened a window of opportunity for patients with first-line therapy failure. However, there is a subset of patients with endometrial cancer who remain insensitive to immunotherapy alone. Therefore, it is necessary to develop new therapeutic agents and further explore reliable combinational strategies to optimize the efficacy of immunotherapy. DNA damage repair (DDR) inhibitors as novel targeted drugs are able to generate genomic toxicity and induce cell death in solid tumors, including EC. Recently, growing evidence has demonstrated the DDR pathway modulates innate and adaptive immunity in tumors. In this review, we concentrate on the exploration of the intrinsic correlation between DDR pathways, especially the ATM-CHK2-P53 pathway and the ATR-CHK1-WEE1 pathway, and oncologic immune response, as well as the feasibility of adding DDR inhibitors to ICIs for the treatment of patients with advanced or recurrent/metastatic EC. We hope that this review will offer some beneficial references to the investigation of immunotherapy and provide a reasonable basis for "double-checkpoint inhibition" in EC.

Vulnerable patients with metastatic colorectal cancer in a real-world setting: A multicenter retrospective study.

114 Background: Several guidelines recommended less intensive chemotherapy for vulnerable patients (pts) with metastatic colorectal cancer (mCRC). However, data in a real-world setting are insufficient particularly for second- or later-line therapies. Methods: This is a multicenter retrospective study of vulnerable pts who were defined to be intolerant to intensive therapy. Vulnerable pts with unresectable mCRC who received vulnerable regimens fluoropyrimidines (FP) with or without biologics, reduced-dose doublet regimens with or without biologics, and anti-epidermal growth factor receptor (anti-EGFR), as first-line therapy between June 2015 and December 2018 were included. Results: A total of 210 pts from 15 Japanese hospitals were enrolled. Their median age, 78 years (range 28-90); male, 57%; ECOG PS 0/1/2, 28/51/21%; right-sided primary tumors, 35%; primary tumor resection, 76%; RAS mutant, 51%. Intolerance to intensive therapy was attributable to older age in 69% of pts, poor PS in 17%, liver and/or renal failure in 24%, and concomitant disease in 30%. First-line regimens such as FP with or without biologics were given to 68%, reduced-dose doublet regimens with or without biologics to 24%, and anti-EGFR monotherapy to 8%. For all pts, the median time to treatment failure (TTF) and overall survival (OS) were 7.6 and 21.4 months, respectively. The response rate (RR) was 31% and the disease control rate was 73%. Despite having a higher RR in doublet regimens with or without biologics, there were no survival differences between FP and doublet regimens (RR 26% vs. 45%, p = 0.03; median TTF 8.2 vs. 7.1 months, p = 0.22; and median OS 23.0 vs. 21.7 months, p = 0.37). Multivariate analysis revealed that ECOG PS2, older age (≥ 80), the presence of ascites, and the number of metastatic sites ≥ 2 were significantly associated with worse OS. Following first-line therapy failure in 195 pts, 74 (38%), 24 (12%), and 13 (7%) pts received vulnerable regimens, full-dose doublet regimens with or without biologics (fit regimens), and other regimens, respectively, as second-line therapy. The median TTF and OS were 4.4 and 13.7 months in vulnerable regimens and 2.6 and 11.7 months in fit regimens, respectively. In 84 pts (43%) who received best supportive care (BSC), the median OS was 3.5 months. Following second-line therapy failure in 84 pts who underwent vulnerable regimens as second-line therapy, third-line chemotherapy was administered to in 42 pts with a median OS of 13.7 months. Conclusions: The efficacy of first-line therapy for vulnerable pts in a real-world setting was comparable to previous studies. Second-line therapy demonstrated clinically significant antitumor activity. Nonetheless, the number of patients who received second- or later-lines chemotherapy was low, and survival in pts who received BSC was dismal.

GNRI Sustainability during One Cycle of First-Line Chemotherapy as a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma

Introduction: This study evaluated the prognostic value of a sustained high Geriatric Nutritional Risk Index (GNRI) during first-line chemotherapy for patients with metastatic urothelial carcinoma (mUC). Methods: Between January 2018 and February 2022, 123 patients received platinum-based chemotherapy at Nagoya City University Hospital and affiliated institutions. Of these, 118 eligible patients who showed an Eastern Cooperative Oncology Group performance status (ECOG-PS) between 0 and 2 were retrospectively examined. Based on body mass index and serum albumin levels, GNRI was calculated immediately before and after the first primary chemotherapy cycle. Patients were divided into two groups based on GNRI: GNRI sustained ≥92 in sustainable (n = 63) and GNRI <92 in unsustainable (n = 55) groups, respectively. Clinical outcomes were compared. Results: No significant differences were noted between the two groups for age, gender, cycle of first-line treatment, and type of series of sequential treatments after failure of first-line therapy. Median overall survival from the start of first-line chemotherapy was 30.2 months (95% confidence interval [CI]: 20.9–NA) for sustainable and 12.6 months (95% CI: 9.0–21.2) for unsustainable groups, respectively (p < 0.05). Multivariate analysis identified ECOG-PS:2 and fatigue, an adverse event, as independent predictors of unsustainable GNRI transition (95% CI: 1.29–90.6, odds ratio [OR]: 10.8; 95% CI: 1.06–26.9, OR: 5.34, respectively). Conclusion: : Sustaining a high level of GNRI was an important prognostic indicator in patients with mUC receiving first-line chemotherapy. Appropriate intervention for controlling adverse events, including fatigue, may enhance physical strength during cancer treatment.