Second-line Treatment In Patients Research Articles

Axicabtagene Ciloleucel As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Primary Analysis of Alycante, a Phase 2 Lysa Study

Background Patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Axicabtagene ciloleucel (axi-cel) has recently demonstrated superiority over standard of care (SOC; salvage chemotherapy followed by HDCT/HSCT in responders) as second-line therapy in patients intended for transplant in the phase 3, ZUMA-7 study (Locke et al, NEJM 2022). The objective of the open-label, phase 2, ALYCANTE study (NCT04531046) was to evaluate the efficacy and safety of axi-cel in patients with R/R LBCL after 1 prior line of therapy not intended for HDCT/HSCT owing to age and/or comorbidities. Methods Eligible patients were adults with R/R LBCL that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥ 65 years; age ≥ 18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥ 18 years and prior ASCT (as 1st line consolidation). Patients received lymphodepletion with cyclophosphamide and fludarabine, followed 2 days later by axi-cel infusion at a target dose of 2 × 10^6 CAR T-cells/kg. Cytokine release syndrome (CRS) and neurological events (ICANS) were graded using the ASTCT grading system. The primary endpoint was the complete metabolic response (CMR) at 3 months from axi-cel infusion based on investigator disease assessment. Results Of 43 patients who underwent leukapheresis, 40 received axi-cel. Median age was 68 years (range, 49-81; 45% ≥ 70 years), 30% had HCT-CI score ≥ 3, and 52.5% were refractory to first-line treatment. Overall, 37 patients (92.5%) received bridging chemotherapy (R-GEMOX for all patients but one). Twenty-seven patients (67.5%) were refractory to bridging therapy, including 15 patients (37.5%) who experienced disease progression upon bridging therapy. Median on-study follow-up was 6.7 months. The study met its primary endpoint with a CMR at 3 months of 67.5% versus 12% expected with SOC based on historical controls (Cazelles et al, Leukemia & Lymphoma 2021). Objective response (OR) rate at 3 months was 75%. Best OR and CR rates were 92.5% and 77.5%, respectively. CRS were seen in 90% of patients, including 10% of grade 3-4. ICANS were seen in 55% of patients, including 17.5% of grade 3-4. Twelve patients (30%) patients were admitted to ICU. Six patients died: 2 due to lymphoma and 4 due to fatal adverse events (COVID-19, mucormycosis, perineal infection, and sepsis). Grade ≥ 3 prolonged cytopenias (i.e. not resolved on Day 29 after axi-cel infusion) occurred in 14 patients (35%). Conclusions In the ALYCANTE study, axi-cel as second-line treatment in patients with LBCL who were not deemed candidates for HDCT/HSCT appears feasible and induces high response rates. Additional exploratory analyses are ongoing, including early PET-CT at Day 14 post-infusion and ctDNA monitoring, which will be presented at the meeting. Finally, the protocol was amended to allow an expansion of 20 additional patients (for a total of 60 patients) to achieve sufficient power to compare 2 subgroups of patients based on age (≥ 70 vs < 70 years).

Combination Therapy with Ruxolitinib and Interferon in Newly Diagnosed Patients with Polycythemia Vera

Background: In the COMBI-I trial, we have shown that the combination treatment of Interferon-alpha-2a (IFN) and ruxolitinib is safe and efficacious in patients with polycythemia vera (PV) and myelofibrosis, who were mostly intolerant or refractory to IFN monotherapy. Interferon-alpha2 (IFN) has been used successfully for decades in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. However, 20-30% of patients are intolerant or show limited response to IFN treatment. Ruxolitinib is an anti-inflammatory agent and is used as first-line treatment in patients with myelofibrosis as well as second-line treatment in patients with PV. Combination therapy with the two agents may be more efficacious than monotherapy. Several reports suggest that after achieving a deep hematological and molecular response, treatment pause for several months to years is safe after IFN treatment. Therefore, an initial high-intensity regimen may help to control the disease allowing for treatment pause or low-dose IFN monotherapy. Herein, we report preliminary safety and efficacy data from the COMBI-II trial in patients with newly diagnosed PV. Aims: To evaluate the safety and efficacy of combination therapy with IFN and ruxolitinib in newly diagnosed patients with PV. Methods: A preplanned interim analysis after at least one year of treatment. Twenty-five patients with newly diagnosed PV were included. They were pretreated according to normal clinical standard with phlebotomies and, if high risk, hydroxyurea before inclusion and initiation of combination treatment. Hydroxyurea was withheld 1 week before initiation of treatment. Patients with severe kidney-, liver-, or heart disease were excluded. Initial therapy was IFN (Pegasys®) 45 μg sc/week and ruxolitinib (Jakavi®) 10 mg BID. The study duration was planned to be two years. Safety was assessed by registering all adverse events graded according to the CTCAE V 5.0. Efficacy was evaluated using the 2013 ELN and IWG-MRT response criteria. The JAK2V617F allele burden was measured using high-sensitivity real-time qPCR on whole blood with a lower detection limit of below 0.1%. Histological response, QoL data, and bone marrow MRI results will be presented in the final report. Results: Twenty-five patients with PV were included in 2019-2021. They had a median age of 70 years; 14 were females and 11 were males. Of the 25 patients, 19 patients were high-risk and 6 were low-risk; 5 patients had previous thrombosis. The median time from accepted referral to initiation of treatment was 67 days. The median follow-up time was 21 months. At time of data evaluation, 13 patients had completed 24 months, while 24 patients had completed 12 months of treatment. One patient was withdrawn from the study early due to the development of myelofibrosis 10 months after beginning treatment. One patient was diagnosed with follicular lymphoma 9 months after initiation of treatment. One patient had an acute myocardial infarction. No other thromboembolic events occurred. No grade 3-4 infections were observed. At follow-up, 19 patients were still receiving combination therapy. One patient was receiving concomitant hydroxyurea; 1 ruxolitinib monotherapy; 1 IFN monotherapy; 1 combination of hydroxyurea and IFN; and 1 hydroxyurea monotherapy. Grade 1-2 anemia was frequent and managed with dose reductions. The median doses of ruxolitinib and IFN at follow-up were 5 mg BID and 45 μg sc/2.week, respectively. High rates of complete hematological response were observed after 1 month of treatment (Figure 1). Three patients required phlebotomy after the first 2 weeks of treatment. The JAK2V617F allele burden was significantly reduced 3 months after the start of treatment, and continued to decline from a median of 47% (95%CI 35-59) at baseline to 6% (95%CI 3-12) after 24 months (figure 2);4 patients had a JAK2V617F allele burden < 1%, and 7 patients had a JAK2V617F allele burden below 5% at the latest measurement. No significant difference in JAK2V617F allele burden was observed between referral and initiation of the combination treatment. Conclusion: Combination therapy with IFN and ruxolitinib is relatively well tolerated and is highly efficacious in newly diagnosed PV patients with frequent normalization of cell counts and a marked reduction of the JAK2V617F allele burden. This therapy could lead to a subsequent long-term approach with low-dose interferon or treatment pauses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer: an open-label, randomized controlled phase 3 trial (ORIENT-3).

Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC. ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)，for sintilimab treatment. Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.

Clinical outcomes of tucidinostat-based therapy after prior CDK4/6 inhibitor progression in hormone receptor-positive heavily pretreated metastatic breast cancer

BackgroundCDK4/6 inhibitors combined with endocrine therapy are standard first- or second-line treatment for patients with HR-positive and HER2-negative advanced breast cancer, however, there is currently no optimal recommendation for therapeutic strategies after progression on CDK4/6i. The aim of this study is to analyze the efficacy and safety of HDAC inhibitor Tucidinostat combined with endocrine therapy in patients after prior CDK4/6 inhibitor progression. MethodsThe pathological and clinical data of 44 HR-positive and HER2-negative breast cancer patients treated with tucidinostat after progression on CDK4/6i at the Breast Oncology Department of the Fifth Medical Center of the PLA General Hospital from July 2019 to October 2021 were retrospectively analyzed. Observation indexes included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR) and adverse events. At the same time, we attempted to identify potential genomic predictors using available next-generation sequencing (NGS). ResultsA total of 44 patients were enrolled in this study. Median follow-up was 10 months (1–26 months) by the data cutoff date (February 2022). The CBR was 6.8% (3/44), the median PFS was 2.0 months (95% CI 1.9–2.1), and the median OS was 14 months (95% CI 6.3–21.7). The mPFS was 4.1 months (95%CI: 0–8.2) in patients with 1 metastatic site, and the mPFS was 4.5 months (95%CI: 4.2–4.8) in patients who received sequential tucidinostat after CDK4/6i failure. Multivariate analysis showed that patients with 1 metastatic site or sequential tucidinostat treatment after failure of CDK4/6i were more likely to benefit from tucidinostat combined with endocrine therapy. Preliminary data showed PIK3CA mutation may be associated with resistance of tucidinostat therapy. No grade 4 adverse events and no treatment-related deaths were recorded in the study. Dose reductions because of adverse events occurred in 4 (9.1%) patients. ConclusionsThis study preliminarily shows that tucidinostat combined with endocrine therapy may be an optional sequential strategy for patients with HR+/HER2-advanced breast cancer that has progressed on CDK4/6 inhibitor, especially for these with lower tumor burden and fewer prior palliative treatment.

A Response to Article Anlotinib Hydrochloride and PD-1 Blockade as a Salvage Second-Line Treatment in Patients with Progress of Local Advanced Non-Small Cell Lung Cancer in Half a Year after Standard Treatment [Letter

Letter for the article Anlotinib Hydrochloride and PD-1 Blockade as a Salvage Second-Line Treatment in Patients with Progress of Local Advanced Non-Small Cell Lung Cancer in Half a Year After Standard Treatment

FOLLOW UP CASES OF BEDAQUILINE IN XDR-TB PATIENTS: NOVEL CASE SERIES

Tuberculosis (TB) is one of the top 10 causes of death and the leading cause from a single infectious agent. Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat. Aglobal total of 2,06,030 people with multidrug or Rifampicin-resistant TB (MDR/RRTB) were detected and notied in 2019. Bedaquiline to be used to treat drug resistant TB.The drug is available as part of second line treatment for patients suffering from MDR-TB and XDR-TB. The drug recently underwent clinical trials at the national level in certain hospitals for safety and efcacy.Because XDR TB is resistant to the most potent TB drugs, the remaining treatment options are less effective, have more side effects, and are more expensive3.

80P RATIONALE-302: Tislelizumab vs chemotherapy as second-line treatment for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC): Impact on health-related quality of life (HRQoL) in Asian patients

Analysis of the intent-to-treat (ITT) population of RATIONALE-302 (NCT03430843) found overall HRQoL, fatigue, and physical functioning were maintained in patients (pts) receiving tislelizumab, while worsening in pts receiving investigator-chosen chemotherapy (ICC). Post-hoc analysis examines HRQoL and ESCC symptoms in the Asian and non-Asian subgroups of pts in RATIONALE-302.

Dutch Gastrointestinal Stromal Tumor (GIST) Registry Data Comparing Sunitinib with Imatinib Dose Escalation in Second-Line Advanced Non-KIT Exon 9 Mutated GIST Patients.

The prognosis of patients with advanced gastrointestinal stromal tumor (GIST) has improved greatly after theintroduction of imatinib. However, primary or secondary resistance to imatinib occurs in the majority of patients. Sunitinib is the standard second line treatment in exon-9 mutated GIST. We compared the clinical outcomes of sunitinib with imatinib dose escalation in patients with progressive advanced non-KIT exon 9 mutated GIST after failure of first line imatinib. A retrospective study was performed, retrieving data from a real-life database (Dutch GIST Registry) including patients with GIST treated with sunitinib or imatinib dose escalation after failure on first line imatinib 400 mg daily. Primary outcome measures were progression free survival (PFS) and overall survival (OS). In total, 110 patients were included, 72 (65.5%) patients were treated with sunitinib (group A) and 38 (34.5%) received an imatinib dose escalation (group B). Important prognostic features at baseline, such as tumor size, stage at diagnosis, mitotic count and localization were equally distributed in both groups. No significant difference (p = 0.88) between median PFS in group A [8.7 months (95% CI 5.6-11.3)] and group B [5.6 months, (95% CI 2.6-8.7)] was observed. Moreover, the OS was similar between group A and group B; 63.2 months and 63.4 months, respectively. This study represents a proper sample size cohort containing detailed data on mutational status of patients with advanced GIST. We illustrated that imatinib dose escalation could serve as a good alternative for sunitinib as second-line treatment in patients with a non-KIT exon 9 mutation.

Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT)

BackgroundVorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of vorolanib and everolimus or vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC). Patients and methodsPatients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1. ResultsBetween 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, vorolanib group and everolimus group, respectively. ConclusionsThe addition of vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile. Trial registrationClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.

Cost-utility analysis of caspofungin and fluconazole for primary treatment of invasive candidiasis and candidemia in Ethiopia

BackgroundInvasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia.MethodsA Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia’s gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings.ResultsIn the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations.ConclusionOur study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.

Response and Survival in Patients of BCLC Stage C Hepatocellular Carcinoma Receiving SBRT and Immunotherapy

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitors (ICI) demonstrated antitumor activity has been increasingly used as first-line or second-line treatments for patients with advanced hepatocellular carcinoma (HCC). In the meanwhile, radiotherapy is turning into a crucial component of multidisciplinary treatment for HCC. Mounting evidence suggests local radiotherapy including SBRT might promote immunogenic tumor cell death and could enhance immunotherapeutic effects in several cancers. However, evidence on advanced HCC is few. Here we report the efficacy and safety of combined SBRT and immunotherapy in patients of BCLC stage C HCC in our center. <h3>Materials/Methods</h3> This is a retrospective analysis of twenty-nine patients with advanced HCC, previously treated with sorafenib or lenvatinib, who received SBRT and anti-PD1 antibody concomitantly or sequentially. Here we report their treatment responses both in-field and outside the radiation field according to RECIST1.1 criteria, progression-free survival (PFS), overall survival (OS), and toxicities. <h3>Results</h3> The median age was 55.1 years (range, 25-75), 90% of patients were male, eighty percent had hepatitis B virus and all patients' Child-Pugh score ≤ B7. Among these patients, twenty-one (70%) had portal vein tumor thrombosis (PVTT), four (13.3%) had inferior vena cava tumor thrombosis and nineteen (63.3%) had extrahepatic metastasis. Eight patients had both extrahepatic metastases and PVTT. 86.2% of patients were also treated with second-line targeted therapy. Tumors treated with SBRT located in liver (52.7%), lung (33.3%), bone (11.2%) and retroperitoneal lymph nodes (2.8%). SBRT administration was a median of 40Gy (range, 25-60) and 5 fractions (range, 3-6). The median follow-up was 16.5 months (range, 6-58). The in-field ORRs were 82.8% and the DCR were 100% (CR 20.7%, PR 62.1%, four bone lesions and one lymph nodes were SD). The out-field ORRs were 27.6% and the DCR were 86.2%. The median PFS was 7 months (95% CI, 1-24 months). Six months PFS rate was 53.3% and 1-year PFS rate was 32.6%. At the time of data cutoff, the median duration of OS has not reached. 1-year OS rate was 62.1% and 2-years OS rate was 50.5%. The prognosis of patients with PVTT was worse than those patients without PVTT (2-years OS rate 35.07% vs 88.89%; p=0.04). Treatment-related AEs consisted of platelet count decrease in four patients, alanine/aspartate aminotransferase increase in five patients and myocarditis in one patient. No SBRT-related grade 3 or higher adverse events occurred. <h3>Conclusion</h3> Our experience suggests that combined SBRT and second line ICI with or without targeted drug can be a safe and effective therapy for BCLC stage C HCC. Further prospective trials are warranted.

Trastuzumab deruxtecan versus trastuzumab emtansine for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: A cost-effectiveness analysis

BackgroundDESTINY-Breast03 (NCT03529110) was the first global phase III study to assess the antitumor activity of trastuzumab deruxtecan (T-DXd) compared to trastuzumab emtansine (T-DM1) in 2022. However, the balance between efficacy and cost of T-DXd remains unclear. As a result, the present study's goal is to investigate the cost-effectiveness of T-DXd vs T-DM1 as a second-line treatment for patients with HER2-positive MBC from the US and Chinese payer's perspectives. MethodsA Markov model with a 20-year time horizon was developed to evaluate the overall cost of patient treatment, incremental cost-effectiveness ratio (ICER), quality-adjusted life-years (QALYs), and life-years (LYs) in the US and China at WTP levels of 150,000/QALY and 37,653/QALY, respectively (3 times GDP per capita in 2021). Key data were gathered from the US government's official website, the Xiangya Hospital of Central South University, and published literature. To determine the model's stability, a sensitivity analysis was performed. A subgroup analysis was also implemented. ResultsCompared with T-DM1, treatment with T-DXd generated an additional 1.672 QALYs (2.796 LYs), resulting in an ICER of $13,342/QALY (US) and $186,017/QALY (China). The cost of drugs is the most influential factor in the American and Chinese models. Subgroup analysis revealed that the T-DXd and T-DM1 regimens were more cost-effective at reducing the risk of death in the US and Chinese HER2-positive MBC patients. ConclusionT-DXd as second-line treatment could gain more health benefits for HER2-positive MBC patients in comparison with T-DM1, which is considered to be cost-effective in the US but not in China.

Pembrolizumab: first anti-PD-1/L1-based regimen for first-line treatment of advanced esophageal cancer in Japan

ABSTRACT Introduction Esophageal cancer (EC) is the ninth most common cancer in Japanese men. Esophageal squamous cell carcinoma (ESCC) is the major histological type and accounts for 90% of EC cases in Japan. The prognosis of advanced ESCC remains poor. The standard treatment for advanced ESCC was palliative chemotherapy with 5-fluorouracil plus cisplatin as first-line chemotherapy. After failure of first-line chemotherapy, taxanes were used as second-line chemotherapy. Recently, pembrolizumab monotherapy has demonstrated benefits as a second-line treatment in patients with advanced ESCC and a combined positive score of ≥10. Survival was found to be improved in patients with advanced EC who received first-line treatment with pembrolizumab plus doublet chemotherapy than in those who received doublet chemotherapy alone. Areas covered This overview of immune checkpoint inhibitors focuses on pembrolizumab in combination with chemotherapy and shares key clinical data relevant to the treatment of patients with EC in Japan. Expert opinion Pembrolizumab plus doublet chemotherapy is now an established first-line treatment for advanced EC in Japan. Recently, nivolumab plus doublet chemotherapy and nivolumab plus ipilimumab have also become first-line treatment options for patients with advanced ESCC. Further investigations are needed to identify biomarkers that would be useful for selecting candidates for these treatments.

Clinical Efficacy of Antianlotinib Combined with Immune Checkpoint Inhibitors in the Treatment of Advanced Non-Small-Cell Lung Cancer and Its Effect on Serum VEGF, CEA, and SCC-Ag.

Purpose This study is aimed at investigating the clinical safety and effectiveness of anlotinib combined with immune checkpoint inhibitors (ICIs) in the treatment of non-small-cell lung cancer (NSCLC). Methods We selected 68 NSCLC patients treated at the Tumor Hospital Affiliated to Nantong University from October 2019 to January 2022. Patients receiving ICI monotherapy were included in the control group (n = 36), whereas patients receiving anlotinib combined with ICIs were enrolled in the study group (n = 32). The survival, adverse reactions (AEs), and short-term clinical effectiveness of the two groups were observed. The tumor markers (vascular endothelial growth factor (VEGF), carcino-embryonic antigen (CEA), and squamous cell carcinoma antigen (SCC-AG)) and T lymphocyte subsets (CD3+, CD4+, CD8+, and CD4+/CD8+) were determined before and after treatment. Results Compared with the control group, the disease-control rate (DCR) and objective response rate (ORR) in the study group were substantially higher than that of the control group (62.50 vs. 36.11, 81.25 vs. 55.56; P < 0.05). The serum levels of VEGF, CEA, and SCC-AG in the two groups were considerably lower after two cycles of treatment (P < 0.05), and the serum levels of VEGF, CEA, and SCC-AG in the study group were significantly lower than those in the control group (P < 0.05). Following therapy, CD8+ in both groups decreased dramatically (P < 0.05), whereas CD3+, CD4+, and CD4+/CD8+ were significantly increased, but there was no statistical difference between the two groups (P > 0.05). The incidence of gastrointestinal, respiratory, cardiovascular, and immune-related adverse events did not significantly differ between the two groups (P > 0.05). The median progression-free survival (PFS) in the control and study groups for the first-line treatment patients was 7.2 and 9.8 months, respectively, whereas for the second-line treatment patients, it was 4.2 and 6.4 months, respectively. The mean PFS of study group was substantially longer than that of the control group regardless of the first- or second-line treatment. According to Cox analysis, the number of drug lines and TNM stage was independent risk variables impacting the prognosis of patients in this study. Conclusion The combination of anlotinib with ICIs was more effective than either agent alone in the first- and second-line treatment of patients with advanced NSCLC. This treatment regimen did not interfere with immunological recovery or increase side effects.

CT-223 Extracorporeal Photopheresis Induces NETosis in Neutrophils Derived From Patients With Graft-Versus-Host Disease

Extracorporeal photopheresis (ECP) serves as a second-line treatment for patients with acute or chronic graft versus host disease (GVHD) and demonstrates efficacy in ameliorating GVHD in this setting. The mechanism by which ECP acts against GVHD is not fully understood. We aimed to assess the influence of ECP on the formation of neutrophil extracellular traps (NETs) among patients with GVHD. We assessed several patients with GVHD who were treated with ECP at Rabin Medical Center. Blood samples were obtained at three different time points: before the onset of an ECP cycle, at the end of the first day of treatment, and 24 hours following the initiation of the ECP treatment cycle. Neutrophils were harvested from all blood samples. NET formation was assessed by measurement of neutrophil elastase activity and by immunofluorescence. Six patients (two women and four men) with chronic GVHD (cGVHD) were included in our study. The underlying hematologic disease was acute myeloid leukemia in four patients, B-cell acute lymphocytic leukemia in one patient, and myelodysplastic syndrome in another patient. We observed a sharp increase in NET formation among all the six patients following ECP. Neutrophil elastase activity level was elevated from a mean value of 2.21mU/mL (+/-0.6mU/mL) at baseline to a mean value of 13.82mU/mL (+/-5.54mU/mL) immediately after the treatment and to a peak value of 17.35mU/mL (+/-10,74mU/mL) 24 hours following the initiation of the ECP cycle. Our preliminary data indicate that ECP induces NET formation among patients with GVHD. Given the central role of neutrophils in the pathogenesis of GVHD, the contribution of NETs to GVHD, and to ECP mode of action, should be further investigated.

OUTCOMES OF SECOND-LINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): RETROSPECTIVE ANALYSIS OF THE BRAZILIAN REGISTRY OF CLL

Real-world data from low and middle-income countries on the management of chronic lymphocytic leukemia (CLL) is needed to understand current clinical practices and unmet needs. Delayed or unequal access to novel agents may negatively impact disease outcomes in (RR) CLL. To describe clinical outcomes of second-line treatment in patients with CLL included in the Brazilian Registry of CLL (BRCLL). Observational study of second-line CLL treatments started between 2006 and 2021. BRCLL is a prospective non-interventional data collection tool. All participant centers registered their CLL patients online, after study approval at each center's ethical review board. Second-line treatments for 444 CLL patients were included. Median age at start of second-line treatment was 66 years (range: 23-93), and 264 were male (59%). Binet staging at CLL was A in 139 patients (36%), B in 139 (36%), and C in 107 (28%). Unmutated IGHV was observed in 61% of patients and FISH was performed in 166 patients (37%), of which 33 patients had del(17p) (20%). The most commonly prescribed regimens were: FC (+/- R) in 160 patients (36%); chlorambucil (+/- R) in 109 (25%); ibrutinib in 63 (14%); CHOP/CVP (+/- R) in 62 (14%); monoclonal antibodies (+/- steroids) in 33 (7%); allogeneic stem cell transplantation in 9 (2%) and venetoclax in 8 (2%). Forty patients (9%) were treated in clinical trials. Median follow-up after second-line treatment was 34 months (range: 3-176). Median time-to-next treatment (TTNT) was 28 months. TTNT was statistically longer in patients who received second-line with ibrutinib or venetoclax in comparison with FC or chlorambucil +/- anti-CD20 (not reached versus 29 months, p < 0.0001) or those who received other regimens (CHOP or CVP +/- anti-CD20, monoclonal antibodies +/- steroids – 12 months, p < 0.0001). Higher 3-year treatment-free survival (TFS) was also observed with ibrutinib or venetoclax (69% versus 41% and 23%, respectively, p < 0.0001). Among patients included in clinical trials, 3-year TFS was also higher (70% versus 38%, p < 0.0001). TFS for patients receiving allogeneic stem cell transplantation was 86% at 3 years. Overall survival (OS) probability at 3 years was 71%. OS was significantly shorter in those who received other regimens (CHOP/CVP-like or monoclonal antibodies +/- steroids; 53%), in comparison with those who received ibrutinib or venetoclax (80%, p < 0.0001), or FC/chlorambucil-based chemotherapy (69%, p = 0.01). Chemotherapy-based second-line CLL treatments were frequent over the reported period, with inferior outcomes for CHOP/CVP-like treatments and monoclonal antibodies with or without steroids. Considering the approval of Bruton tyrosine kinase and BCL2 inhibitors in recent years, a shift towards targeted agents in RR CLL is anticipated, but cannot be established at this time for the majority of patients in second line reported to the BRCLL. While the adoption of targeted therapies was associated with longer TTNT and OS, access to these agents is still very limited in our setting.

Anlotinib Hydrochloride and PD-1 Blockade as a Salvage Second-Line Treatment in Patients with Progress of Local Advanced Non-Small Cell Lung Cancer in Half a Year After Standard Treatment.

PurposeAs for local advanced non-small cell lung cancer (NSCLC), synchronous radiotherapy and chemotherapy is the standard treatment mode. But for patients with progress in half a year, which means the second-line chemotherapy effect is not ideal for them. We observed the efficacy and safety of anlotinib hydrochloride combined with PD-1 blockade as the second-line treatment for those patients in this trial.Patients and MethodsFrom January 2018 to December 2019, 57 patients with the progress of local advanced NSCLC treated with anlotinib plus PD-1 blockade until disease progression or intolerance as a result of adverse events. Patients have been assessed using computed tomography prior to treatment and during follow-up every 2 months until disease progression or death. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety. Survival curves were created using the Kaplan–Meier method.Results57 patients were enrolled. The median age was 64 years, and 61.4% of the patients were men. The ORR was 50.9% with a median OS time of 14 months and the 1-year OS rates and PFS rates were 81.8% and 33.3%, respectively. The patients with squamous cell carcinoma, no brain or liver metastases had longer PFS than patients with liver metastasis. When the PFS was calculated from the time of second treatment, the median PFS was 9 months. Most adverse events (AEs) were grade 1–3, one drug-related death was noted.ConclusionThe expected outcome of this study is that anlotinib combined with PD-1 blockade has tolerable toxicity and better ORR, OS than second-line chemotherapy. The results may indicate additional treatment options for patients with progress of local advance NSCLC in half a year after standard treatment.

Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study.

BackgroundTopoisomerase is an essential enzyme for deoxyribonucleic acid replication, and its inhibitors suppress tumor progression. Amrubicin, a topoisomerase II inhibitor, is mainly used in the second-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). However, the impact of different types of topoisomerase inhibitors for first-line chemotherapy on the efficacy of amrubicin remains unclear. In the present study, we aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors.MethodsThis study retrospectively analyzed patients with ES-SCLC who experienced recurrence and were treated with amrubicin at 22 institutions in Japan between April 2015 and November 2020. The progression-free survival of amrubicin monotherapy was investigated using the Kaplan-Meier method.ResultsA total of 320 patients were enrolled in this study, with 59 (18%) receiving platinum plus topoisomerase I inhibitor irinotecan and 261 (82%) receiving platinum plus topoisomerase II inhibitor etoposide as first-line treatment. The progression-free survival of amrubicin was significantly longer in the irinotecan group than in the etoposide group (3.2 vs. 2.5 months; P=0.034).ConclusionsThese results showed that different types of topoisomerase inhibitors could affect the efficacy of amrubicin monotherapy in the second-line treatment of patients with relapsed ES-SCLC.

848P Second-line systemic treatment for patients with advanced melanoma: Results from the prospective real-world study GEM1801

Information regarding charatcteristics and outcomes of second line treatment for patients with advanced melanoma is scarce since no randomized clinical trials are published in the post-targeted and immunotherapy era. Real-world data studies are capital for benchmarking patients´ outcomes in order to design clinical trials in this scenario. GEM1801 is a prospective observational real-world study that currently has included 551 patients with advanced melanoma treated in 37 centers from the Spanish Melanoma Group (GEM). This is a descriptive analysis of basal characteristics, progression free survival (PFS) and overall survival (OS) from patients that received second line treatment in GEM1801. 186 (33.8%) patients received a second line (2L) treatment. For the 186 patients receiving 2L, with a median follow up of 6.4 months (m) (95% CI: 4.9-9.8), median PFS was 4.7 m (95% CI: 3.5-5.8) and median OS 11.3 m (95% CI: 8.6-13.4) from the beginning of 2L. Additionally, 63 (33.9%) patients received treatment beyond 2L. Table summarizes the patients characteristics and their outcomes according to BRAF status and treatments. For the 365 (66.2%) patients that did not receive 2L, the reasons were: 249 (68.2%) no progression with first line; 110 (30.1%) death before 2L; 6 (1.6%) loss of follow up.Table: 848PCHARACTERISTIC AT 2LBRAF Mutated N= 99BRAF wildtype N= 82SEX female N (%)47 (47.5)33 (40.2)age (median, Rank)59 (23-90)69 (29-93)ECOG 0-1 N (%)87 (87.9)78 (95.1)LDH >UNL N (%)34 (34.3)26 (31.7)M1C-D N (%)62 (62.6)40 (48.8)2L targeted therapy (TT): N, (%)44 (44.4)2 (2.4)TT mPFS, m (95% CI)12.4 (6.1-NR)2 (NA-NA)TT mOS, m (95% CI)20 (11.5-NR)2.7 (NA-NA)2L immunotherapy (IT): N (%)46 (46.5)34 (41.5)IT mPFS, m (95% CI)5.3 (2.9-10.8)3.1 (2.3-8.2)IT mOS, m (95% CI)10.9 (3.7-NR)12.5 (8.1-NR)2L Chemotherapy (CT): N, (%)4 (4)29 (35.4)CT mPFS, m (95% CI)0.4 (0-NR)3.2 (2.7-5.5)CT mOS, m (95% CI)0.6 (0.2-NR)5.6 (3.9-15.2)2L non specified: N (%)5 (5.1)13 (15.9)Treatment beyond 2L N (%)27 (27.8)33 (39.3)There are 5 patients with unknown BRAF status. Open table in a new tab There are 5 patients with unknown BRAF status. Second line treatment is still a difficult clinical scenario, especially for patients with BRAF wildtype melanoma and with BRAF mutated that progress after targeted therapy. The results, remarkably for PFS, need to be improved, thereby clinical trials participation is encouraged.

OA04.06 PEMbrolizumab Plus Lenvatinib In Second And Third Line Malignant Pleural MEsotheLiomA Patients: A Single Arm Phase II Study (PEMMELA)

There is a need for effective second line treatment in patients with recurrent malignant pleural mesothelioma (MPM). Pembrolizumab, a PD-1 receptor blocker, has shown a response rate up to 20% as monotherapy. Lenvatinib, a multiple tyrosine kinase inhibitor with mostly vascular endothelial growth factor receptor (VEGFR) blocking properties, has synergistic interactions with PD-1 blocking in other tumors. We aimed to evaluate clinical activity and toxicity of pembrolizumab plus lenvatinib in patients with recurrent MPM.