Second-line Group Research Articles

Outcomes of Radiotherapy in Oligoprogressive Breast Cancer.

Radiotherapy (RT) shows potential for improving local control in cases of oligoprogressive metastatic breast cancer (mBC). This retrospective analysis aims to evaluate the advantages of RT in such a clinical scenario. We conducted a retrospective analysis including patients with mBC who received radiation therapy (RT) for up to three sites of oligoprogression while continuing systemic therapy. The study took place between January 2014 and December 2021. Our endpoints were progression-free survival after radiotherapy (PFS-AR), the rate of discontinuation of systemic therapy (RDT) at three months post-RT, and overall survival (OS). We used Cox regression analysis to perform multivariate analysis for PFS-AR. Fifty-nine patients met the inclusion criteria. The PFS-AR was 13 months (95% CI 8.5-18.8 months). At three months, the RDT was 3% (two patients). A significant difference in median PFS-AR was observed between patients in the first + second-line group and those in the subsequent line group (p = 0.03). In the multivariate analysis conducted for PFS-AR, the biologically effective dose (BED) with α/β = 4 > 100 Gy emerged as the sole significant variable (p = 0.0017). The median overall survival (OS) was 24.4 months (95% CI 17-24.4 months). This study is the first report on the outcomes of radiotherapy in a cohort of over 50 patients with oligoprogressive metastatic breast cancer (mBC). Our findings emphasize the significant relationship between PFS-AR, the number of ongoing lines of systemic therapy, and the BED of radiotherapy.

Efficacy and Safety of Salvage-line Nivolumab Monotherapy for Advanced Esophageal Squamous Cell Carcinoma: Comparison of 240 mg Versus 480 mg Doses

BackgroundNivolumab monotherapy is the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240 mg every 2 weeks was approved initially, followed by fixed dosing with 480 mg every 4 weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited.MethodsWe compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line (n = 85) or later-line (n = 32) nivolumab monotherapy at our institution between January 2016 and December 2021.ResultsIn the second-line group, patient characteristics for the 240 mg and 480 mg groups were as follows (240 mg vs. 480 mg): performance status (PS) 0/1/2 was 34/61/5% vs. 54/42/4%, and prior fluoropyrimidine plus platinum therapy (FP) was 81.3% vs. 42.3%. In the later-line group, the characteristics were: PS 0/1/2 was 28/60/12% vs. 14/86/0%, and prior FP was 60.0% vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p = 0.19) and 0 vs. 14.3% in the later-line group (p = 0.22). Median PFS was 1.7 vs. 4.1 months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35–1.01, p = 0.056) and 1.4 vs. 1.8 months on later-line (HR 0.58, 95% CI 0.23–1.46, p = 0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively.ConclusionsThe efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC.

Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study

BackgroundA recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2− advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2− ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice.MethodsReal-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2− ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival.ResultsOf the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9–29.4) for first-line and 14.5 months (10.2–19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1–87.7), 82.0% (70.7–89.3), and 66.0% (57.9–72.9), respectively.ConclusionThe addition of palbociclib to ET was effective for treating HR+/HER2− ABC in Japanese routine clinical practice.

The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment

To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

Efficacy and safety of first-line or second-line selective laser trabeculoplasty for normal-tension glaucoma: a multicentre cohort study

Background/aimsThis study aimed to investigate and compare the efficacy and safety of first-line and second-line selective laser trabeculoplasty (SLT) in Japanese patients with normal-tension glaucoma (NTG).Methods100 patients with NTG were...

Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study.

Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

Analysis of the Efficacy, Progression-Free Survival, and Safety of Anlotinib in Advanced Lung Cancer Treatment

Objective: To analyze the clinical efficacy, progression-free survival, and safety of anlotinib in the treatment of advanced lung cancer. Methods: A retrospective analysis was conducted using data from 60 patients with advanced lung cancer treated with anlotinib from May 2019 to May 2021. This analysis aimed to comprehensively evaluate the clinical efficacy, progression-free survival, and adverse reactions of anlotinib. Results: The median progression-free survival (PFS) for the 60 patients was 5.79 months, with an overall response rate (ORR) of 21% and a disease control rate (DCR) of 90%. In the first-line group, the median PFS was 6.20 months, ORR was 76.92%, and DCR was 84.61%. The second-line group showed a median PFS of 6.30 months, ORR of 28.57%, and DCR of 90.48%. In the third-line group, the median PFS was 5.34 months, ORR was 19.23%, and DCR was 92.30%. The single-agent group exhibited a median PFS of 5.09 months, ORR of 23.33%, and DCR of 76.67%. In the combination group, the median PFS was 6.53 months, ORR was 46.67%, and DCR was 100%. The combination group demonstrated a significantly higher medication effect than the single-drug group, and adverse drug reactions were mostly grade 1–2. Conclusion: Anlotinib exhibits a better disease control rate and survival benefit in the treatment of advanced lung cancer. The combination effect is superior to monotherapy, with relatively controllable adverse effects.

Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial

Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma. TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete. Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5-34·8), 39 (36%, 90% CI 28-44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24-40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3-4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia. In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy. Bristol Myers Squibb.

The Efficacy and Safety of Ramucirumab in Heavily Pretreated Advanced Hepatocellular Carcinoma.

Ramucirumab has been approved for the management of hepatocellular carcinoma (HCC) after progression on sorafenib; however, the data on ramucirumab in heavily pretreated HCC are limited. This study aimed to investigate the real-world efficacy and safety of ramucirumab in patients with heavily pretreated advanced HCC. Patients with advanced HCC who received intravenous ramucirumab as second-line and later therapy were retrospectively reviewed. Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Additionally, prognostic factors were estimated using hazard ratios with 95% confidence intervals. In total, 31 patients with advanced HCC who received ramucirumab were enrolled, including 11 patients with second-line treatment and 20 with third-line and later-line treatment. The objective response rate was 3.2% with a disease control rate (DCR) of 45.2%, and the DCR of ramucirumab between the second-line group and the third-line and later-line groups did not differ. The median PFS and OS were 2.1 months and 6.7 months, respectively, in the whole population. In the multivariate analyses, alpha-fetoprotein <1,000 ng/ml was an independent prognostic factor for better PFS and OS. All adverse events were classified as grade 1-2 without grade 3-4 toxicities or drug-related mortality. Additionally, 51.6% of patients received subsequent therapy after progression on ramucirumab. The results of our study show the efficacy and safety of ramucirumab in patients with heavily pretreated HCC in real-world practice.

Vibegron 50 mg Once Daily Improves OABSS, OAB-q SF Score in OAB Patients ≥80 Years Old in Real-World Clinical Settings and Switching from Other OAB Drugs May Reduce Residual Urine Volume.

The treatment effects of vibegron have not previously been evaluated in a prospective, non-interventional observational study of elderly Japanese patients, particularly those ≥80 years old. In addition, no reports have referred to residual urine volume in switching cases. We therefore grouped patients by condition and investigated the treatment effects of vibegron on Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and residual urine volume in each group. This multicenter, prospective, non-interventional, observational study consecutively enrolled OAB patients with total OABSS score ≥3 and OABSS question 3 score ≥2. Sixty-three patients from six centers were recruited. Vibegron 50 mg once daily was administered for 12 weeks as first-line monotherapy (first-line group), monotherapy switching from antimuscarinics or mirabegron due to failure of prior therapy (no washout period), or combination therapy with antimuscarinics (second-line group). OABSS, OAB-q SF, and residual urine volume were collected after 4 and 12 weeks. Adverse events were also recorded at each visit. Of the 63 patients registered, 61 were eligible for analysis (first line, n=36; second line, n=25). The OABSS, excluding daytime frequency scores, and OAB-q SF scale showed significant improvement in all conditions. Switching from mirabegron to vibegron significantly reduced residual urine volume. No serious treatment-related adverse events were encountered. Vibegron 50 mg once daily significantly improved OABSS and OAB-q SF even in patients ≥80 years old. Notably, switching from mirabegron to vibegron resulted in significant improvements to residual urine volume.

Effectiveness and safety of immune checkpoint inhibitor monotherapy in advanced upper tract urothelial carcinoma: A multicenter, retrospective, real-world study.

The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in advanced upper tract urothelial carcinoma (UTUC) is less reported. In total, 106 consecutive advanced UTUC patients receiving ICI monotherapy were collected from nine high volume centers. Clinical outcomes were analyzed according to multiple parameters (e.g., treatment line, metastatic sites). Objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were captured after ICI initiation. With a median follow-up of 12.0months, 25 patients in the first-line group and 15 patients in the second-line group died of UTUC. We reported a median OS of 18.0months, a median PFS of 5.0months, and an ORR of 38.6% for patients in the first-line group; a median OS of 10.0months, a median OS of 4.0months, and an ORR of 27.8% for patients in the second-line group. Complete response was observed in two patients in the first-line group and one patient in the second-line group with a total complete response rate of 2.8%. In the univariate and multivariate analysis, visceral metastasis with a hazard ratio of 2.4 was associate with poor OS. The most common treatment-related adverse events included fatigue (11.3%), pruritus (10.4%), and diarrhea (6.6%). This real-world study suggests that ICI monotherapy is active and has acceptable toxic effects for unresectable or metastatic UTUC as first-line therapy in cisplatin-ineligible patients or second-line therapy in platinum-refractory patients.

A prospective study exploring the safety and efficacy of lenvatinib for patients with advanced hepatocellular carcinoma potential in current real-world practice.

512 Background: Lenvatinib has been widely used as a leading oral multikinase inhibitor for advanced hepatocellular carcinoma (HCC) patients in real-world practice worldwide. However, in the global phase 3 study comparing the effectiveness of lenvatinib and sorafenib, only a limited population of patients were enrolled, excluding those who had a high-burden intrahepatic lesion or Child-Pugh class (C-P) B, who were likely to receive systemic therapy in the clinical practice. Currently, combination immunotherapy has replaced multikinase inhibitors as the standard first-line treatment. Therefore, this prospective study explored the safety and efficacy of lenvatinib in the patient population, which would be used in real-world practice. Methods: This was an open-label, multicenter, prospective study that enrolled patients who had advanced HCC with C-P A or B, treated with lenvatinib as first-line or second-line after atezolizumab plus bevacizumab (Atz + Bv) at 10 sites in Japan. The study included patients who had high tumor burden, defined as identifying either tumor volume of more than 50% of the liver, portal vein tumor thrombosis reaching the main trunk or the contralateral branch, or bile duct invasion at baseline (jRCTs031190017). Results: Between December 1, 2019, and September 30, 2021, 59 patients were recruited for this study. At the time of enrollment, 47 and 12 patients were classified as C-P A and B, respectively. This study included 11 patients with high tumor burden and 12 treated with second-line after Atz + Bv. All patients with high tumor burden and second-line treatment were classified as C-P A. Median overall survival of C-P A and B patients was 20.3 and 4.2 months, respectively. Similarly, progression-free survival according to modified RECIST (mRECIST) of C-P A and B patients was 4.8 and 2.8 months, respectively. Objective response rate (ORR) according to mRECIST in C-P A patients was 61.9%, whereas in C-P B patients was 25.0%. ORRs of high-burden group and second-line group were 80.0% and 40.0%, respectively. Major severe adverse events (AE) (≥grade 3) in C-P A patients were hypertension (41.3%) and proteinuria (23.9%). In contrast, those in C-P B patients were hyponatremia (41.7%), elevated aspartate aminotransferase (41.7%), hypertension (33.3%), decreased appetite (16.7%), diarrhea (16.7%), and proteinuria (16.7%). Discontinuation rate due to AE of C-P A and B patients was 17.4% and 33.3%, respectively. In high-burden and second-line groups, 10% and 20% discontinued lenvatinib due to AE, respectively. Conclusions: Lenvatinib is expected to be safe and effective in patients with advanced HCC who have a high tumor burden and second-line treatment after Atz + Bv, whereas liver function was maintained with C-P A. However, in C-P B, this study found lower efficacy and higher discontinuation rates due to AE compared with C-P A. Clinical trial information: s031190017 .

Impact of Early Hospitalization, Medical Comorbidities and Allogeneic Stem Cell Transplantation on Survival in Acute Myeloid Leukemia Patients Treated with Venetoclax Based Therapy - a Single Institution Experience from an Academic Center

Introduction: Bcl-2 inhibitor Venetoclax (Ven) in combination with hypomethylating agents (HMA) has improved response rates (RR), and median overall survival (OS) in Acute Myeloid Leukemia (AML) patients who are elderly and/or ineligible for intensive therapies. However, observed outcomes in patients treated in off-trial setting may be inferior (Winters, et al 2019). While disease markers that predict poor RR are well described, patient factors that could impact the inferior outcomes in the real-world setting have not been fully understood. We investigated the impact of incremental age, early hospitalization, comorbidity burden, along with other disease and treatment variables, on survival. Patients and methods: After IRB approval, all consecutive patients with AML and high-risk myelodysplastic syndromes (MDS) who were treated with Ven based regimen between 2017 and 2021 were reviewed. Descriptive statistics are reported. Kaplan-Meir analysis was used to estimate survival, and cox-proportional hazards was used to investigate survival association with variables. Overall survival (OS) was calculated from the time of initiation of venetoclax to the date of last follow up or death. Disease related data, effect of Incremental age, number of medical co-morbid conditions, unplanned early hospitalization (EH) rates within 30 days (EH30) and 90 days (EH90), causes of hospitalization, transfusion needs, and other treatment related adverse events were captured. Factors that impacted EH and overall survival were investigated. Results: Baseline characteristics are outlined in Table 1. A total of 89 subjects with AML and MDS-EB2 who received Ven based therapy were identified. All but 3 received HMA/Ven combination. Forty-nine (55%) received HMA/Ven in first line (FL) and 40(45%) in second line (SL) or later, of whom 12(30%) were treated in post- transplant (ASCT) relapse. Median age was 72 and 64, and median follow up was 21 months (95% CI, 9,27) and 22 months (95% CI, 9,32), respectively, for FL and SL. By ELN criteria high risk patients were 77% and 57% in FL and SL cohorts, respectively. Sixty percent and 40% patients had EH30 and 52%, and 35% patients had EH90 in FL and SL cohorts, respectively. Presence of ≥2 comorbidities significantly predicted EH90 (p=0.04). Most common cause of EH was neutropenic fever and sepsis. In 20 patients where data was available, median pRBC units received were 6(range 1-32), and 10(range 0-50), and median platelet units were 8(range 0-42), and 1 (range 0-73), in FL and SL cohorts, respectively. Table 2 summarizes survival outcomes by important variables. Median OS is 6 months (95% CI, 4,10), and 8 months (95% CI, 4,11) for the entire FL and SL groups. Within the SL group, median OS was significantly worse at 4 months (95% CI 0,8) Vs 11 months (95% CI, 4,13) for those who previously received an ASCT vs those who did not (p=0.02). In FL patients, increasing age (10 vs 5 months, p=0.03) and poor therapy response (11 vs 2 months, p<0.0001) had significant impact on survival, while in SL group TP53mut (13 vs 4 months, p=0.04) and poor response (8 vs 2.5 months p=0.04) were significant predictors of poor OS. On multivariate analysis (MVA), only TP53mut (p=0.04), and response (p=0.003) retained significant impact on OS in both FL and SL cohorts. While EH90 and presence of ≥2 comorbidities also trended towards lower survival, they did not reach statistical significance. Incremental age had no impact on OS in MVA. Following remission, ASCT Vs no-ASCT resulted in an improved survival, with a median OS of 15 months (95%CI 0,19) vs 5 months (95% CI 3,9), p=0.09; and NR (95% CI 3, NR months) Vs 6 months (95% CI 4, 8), p=0.04, In both FL and SL cohorts respectively. Conclusions: We comprehensively evaluated disease and patient factors, and their impact on hospitalization, and on OS in AML patients during Ven based therapy. EH and transfusions were common, without an impact on OS. Age had no impact on EH or OS, but comorbidity burden increased EH risk. High risk disease and poor response to therapy resulted in poor OS. ASCT was crucial for prolonged OS in both FL and SL cohorts. One likely cause of inferior OS noted in FL patients could be the lower rate of ASCT. Our results could provide better understanding to optimize Ven based therapy, and improve early treatment related toxicities in the real-world setting. Quality of life and health care utilization burden associated with this regimen needs to be studied systematically. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Significance of timing of therapeutic line on effectiveness of nivolumab for metastatic renal cell carcinoma.

This study aimed to clarify the significance of therapeutic timing on the effectiveness of nivolumab for treating metastatic renal cell carcinoma. Fifty-eight patients with metastatic renal cell carcinoma treated with nivolumab monotherapy were retrospectively studied. Patients who were treated with nivolumab as second-line therapy were included in the second-line group, while the others were included in the later-line group. The clinicopathological characteristics, effects of nivolumab, and prognoses of these groups were compared. Twenty and thirty-eight patients were included in the second-line and later-line groups, respectively. There were no significant differences in the distribution of International Metastatic Renal Cell Carcinoma Database Consotium risk and other clinicopathological characteristics between the 2 groups. The proportion of patients whose objective best response was progressive disease in the second-line group was significantly lower than that in the later-line group (15% vs. 50%, p = 0.0090). The 50% progression-free survival with nivolumab in the second-line group was significantly better than that in the later-line group (not reached and 5 months, p = 0.0018). Multivariate analysis showed that the second-line setting was an independent predictive factor for better progression-free survival (p = 0.0028, hazard ratio = 0.108). The 50% overall survival after starting nivolumab in the second-line and later-line groups was not reached and 27.8 months, respectively (p = 0.2652). The therapeutic efficacy of nivolumab as second-line therapy is expected to be better than that of later therapy.

Management of checkpoint inhibitor toxicity and survival in patients with advanced melanoma.

9546 Background: Management of checkpoint-inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of immunosuppressive treatment with anti-TNF on checkpoint-inhibitor efficacy. Methods: Advanced melanoma patients experiencing grade ≥3 irAEs after treatment with first-line ipilimumab-nivolumab between 2015 and 2021 were included from the Dutch Melanoma Treatment Registry. Progression-free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS) were analyzed according to toxicity management regimen. A cox proportional hazards model was used to account for the confounders age, sex, performance status, lactate dehydrogenase, site of metastases and type of irAE. Results: Out of 771 ipilimumab-nivolumab treated patients, 350 were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids only and 115 received steroids with second-line immunosuppressants consisting of anti-TNF, mycophenolic acid, tacrolimus and other immunosuppressants. Median PFS was significantly longer for patients treated with steroids (11.3 months) than for patients treated with steroids and second-line immunosuppressants (5.4 months; HR 1.43; 95%CI 1.07-1.90; p = 0.01). Median OS was also significantly longer for the steroids group (46.1 months) than for the steroids and second-line immunosuppressants group (22.5 months; HR 1.64; 95%CI 1.16-2.32; p = 0.005). Results for MSS were similar (not reached versus 28.8 months; HR 1.70; 95%CI 1.16-2.49; p = 0.006). Median PFS, OS and MSS are shown in Table 1. After adjustment for potential confounders, patients treated with steroids + second-line immunosuppressants showed a non-significant trend towards a higher risk of progression (HRadj 1.40; 95%CI 1.00-1.97; p = 0.05), a higher risk of death (HRadj 1.54; 95%CI 1.03-2.30; p = 0.04) and of melanoma-specific death (HRadj 1.62; 95%CI 1.04-2.51; p = 0.032) compared to the steroids group. Conclusions: Second-line immunosuppression for irAEs is associated with impaired PFS, OS, and MSS in advanced melanoma patients treated with first-line ipilimumab-nivolumab, irrespective of being anti-TNF or other second-line immunosuppressants. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in melanoma but also in other tumor types. [Table: see text]

Comparison of follow-up treatment regimens for colorectal cancer liver metastases without objective response to neoadjuvant chemotherapy: direct surgery or surgery after second-line chemotherapy

Objective: To compare the effect of direct surgery or surgery after second-line chemotherapy for colorectal cancer patients with liver metastases who did not achieve objective remission after neoadjuvant chemotherapy. Methods: A retrospective case cohort study was used. The clinical and pathological data of 107 patients with colorectal cancer liver metastases who did not achieve objective response to neoadjuvant chemotherapy at Department of Hepatobiliary Surgery,Cancer Hospital,Chinese Academy of Medical Sciences from December 2008 to December 2016 were retrospectively collected. There were 71 males and 36 females, median age was 57 years (range: 28 to 79 years). According to the different treatment regimens after neoadjuvant chemotherapy,107 cases were divided into a direct surgery group (direct group,n=65) and an operation after receiving second-line chemotherapy group (second-line group,n=42). The propensity score matching(PSM) of the Logistic regression model was used to match the bilobar distribution of liver metastases and the number of first-line chemotherapy cycles in the two groups of patients. The caliper value was set to 0.10 and the matching ratio was 1∶2. T test, Mann-Whitney U test, χ2 test or Fisher's exat test was used to analyzed the data between the tuo groups, respectively. Survival analysis design was used to investigate the difference in prognosis between the two groups of patients. Results: The follow-up time(M(IQR)) was 56.3(34.3) months (range: 2.1 to 95.0 months),and all patients were followed up. After PSM,there were 28 cases in the direct group and 42 cases in the second-line group, there were no significant differences in whether R0 resection was feasible,blood loss,blood transfusion,postoperative complications and postoperative hospital stay between the two groups (all P>0.05). The 1,3,and 5-year progression-free survival(PFS) rates of the direct group were 40.0%,16.5%,and 11.0%,and the 1,3,and 5-year overall survival(OS) rates were 98.5%,61.2%,and 41.4%,respectively, the second-line group 1,3,5 years PFS rates were 35.7%,14.3%,14.3%,1,3,5-year OS rate were 95.2%,55.1%,44.4%,respectively. The median PFS time of the direct group and the second-line group was 8.5 months and 7.5 months,respectively,and the difference was not statistically significant (P=0.826). The median OS time of the direct group and the second-line group were 33.8 months and 46.9 months,respectively. The difference was not statistically significant(P=0.646).The median PFS time of the direct group and second-line chemotherapy complete remission and partial remission group(CR/PR group) was 10.2 months and 9.1 months,respectively,and the difference was not statistically significant(P=0.669). The median OS time of the direct group and the second-line CR/PR group was 51.0 months and 46.9 months,respectively,and the difference was not statistically significant(P=0.427). The results of survival analysis suggested that major liver resection was an independent prognosis factor for PFS (HR=1.809,95%CI: 1.067 to 3.067,P=0.028) and OS(HR=2.751,95%CI: 1.317 to 5.747,P=0.007). Second-line chemotherapy was not an independent prognostic factor for PFS (HR=0.945, 95%CI:0.570 to 1.567,P=0.828) and OS (HR=0.866,95%CI: 0.468 to 1.602,P=0.646). Conclusions: There is no significant difference in the short-term outcome and long-term prognosis between direct surgery patients and second-line chemotherapy followed by surgery. Second-line chemotherapy is not an independent prognostic factor for colorectal cancer liver metastases patients who fail to achieve objective response after neoadjuvant chemotherapy.

Analysis of the Curative Effect and Influencing Factors of Nilotinib Second-line and Dasatinib Third-line on Chronic Myelogenous Leukemia Failed First-line and Second-line Treatment

To evaluate the efficacy of the second-line nilotinib and third-line dasatinib on chronic myelogenous leukemia (CML) with failed first- and second-line treatments, and analyze the influencing factors of the efficacy. Selected 83 patients in The Third People's Hospital of Kunshan City, Jiangsu Province with CML who were treated with nilotinib as the second-line treatment after the failure of the first-line treatment with imatinib as the second-line treatment group (referred to as the second-line group) from January 2014 to December 2018, and 61 CML patients who were treated by dasatinib as the third-line treatment group (referred to as the third-line group) after the failure of the second-line treatment with nilotinib; the first-line treatment with imatinib failed, but due to various reasons, the patients were fully after being informed of the possible serious consequences of not changing the drug treatment, 37 CML patients who were still required to continue imatinib treatment served as the control group. The hematological, genetic and molecular responses of each group were compared for 3, 6, and 24 months of treatment. LogistiC regression was used to analyze the factors affecting the second and third line curative effects. The three groups had statistically significant differences in the rates of achieving CHR, MCyR, and MMR at 3, 6, and 12 months of treatment (P<0.05). Compared the two groups, the CHR rates of the second-line group at 3, 6, and 12 months of treatment were 100.00%, 97.59%, and 95.18%, respectively; higher than the third-line group's 90.16%, 86.89%, 83.61% and the control group's 83.78%, 75.68% and 72.97%; the CHR rate of the third-line group was higher than that of the control group at 6 and 12 months of treatment. The rates of reaching MCyR at 3, 6, and 12 months after treatment in the second-line group were 87.95%, 93.98% and 93.98%, respectively, while those in the third-line group were 80.33%, 88.52% and 86.89%, which were higher than those of the control group of 67.57%, 64.86% and 48.65%. The rates of achieving MMR at 3, 6, and 12 months of treatment in the second-line group were 19.28%, 33.72% and 60.24%, respectively, and those in the third-line group were 11.48%, 26.23% and 49.18%, which were higher than those of the control group of 0.00%, 2.70% and 0.00%; The rate of reaching MMR within 12 months of treatment in the second-line group was higher than that of the third-line group, and the differences was statistically significant (P<0.05). There was no significant difference in the rate of reaching MCyR between the second-line group and the third-line group at 3, 6, and 12 months, and the rate of reaching MMR at 3 and 6 months (P>0.05). The incidence of nausea and vomiting among the three main non-hematological adverse reactions, and the incidence of grade 1~2 anemia among the hematological adverse reactions were statistically significant (P<0.05). There was no significant difference in the incidence of rash, eyelid edema, diarrhea, thrombocytopenia, leukopenia and neutropenia in the three groups (P>0.05). The incidence of nausea and vomiting and grade 1~2 anemia in the second-line group and the third-line group were higher than that of the control group, and the difference was statistically significant (P<0.05). There were statistically significant differences in Sokal score, medication compliance, and hematological adverse reactions between the MMR group and the non-MMR group (P<0.05). Logistic regression analysis showed that dose reduction or withdrawal during the treatment period, and grade 3~4 hematological adverse reactions were the main factors affecting the second and third line curative effects (OR=22.160, 2.715, 95% CI=2.795-93.027, 1.882-48.834). The second-line nilotinib and the third-line dasatinib have a better effect on CML patients who have failed the first and second-line treatments. Grade 3~4 hematological adverse reactions, dose reduction or withdrawal are risk factors that affect the efficacy of second and third-line treatments.

Safety and Efficacy of Lenvatinib Plus Nivolumab in Unresectable Hepatocellular Carcinoma: A Retrospective Study in China

Introduction: Combining lenvatinib and programmed cell death-1 immune checkpoint represents a promising treatment strategy for patients in unresectable hepatocellular carcinoma (uHCC). We investigated the efficacy and safety of combined lenvatinib and nivolumab in uHCC in China. Method: Between June 3, 2019, and May 31, 2021, 66 patients received lenvatinib plus nivolumab as first-line and second-line treatment for the uHCC retrospectively analyzed. Patients initiated lenvatinib (8 mg for bodyweight < 60 kg or 12 mg for bodyweight ≥ 60 kg) 3-7 days to confirm tolerability, and then received 14-day treatment cycles of nivolumab (3 mg/kg bodyweight by IV infusion). Results: All the patients had BCLC Stage C. Lenvatinib plus nivolumab was used as first-, second-line treatments in 36 (54.5%) and 30 (45.5%), respectively. An objective response rates (ORR) was recorded in 23 patients (34.8%), while the best overall responses were from 4 complete response (CR) and 19 partial responses (PR), 32 (48.5%) participants had stable disease (SD). Furthermore, the ORR and disease control rates (DCR) in the first-line group were 36.1% and 86.1%, respectively. The ORR and DCR in the second-line group were 33.3% and 80%, respectively. Two patients without extrahepatic metastasis achieved sufficient downstaging to be converted to resectable disease and received curative hepatectomy. One of them achieved pathological CR. All adverse events were expected and manageable, and no treatment-related deaths were reported. Conclusion: Combination lenvatinib with nivolumab showed promising antitumor activity and manageable toxicity in patients with uHCC. Further randomized, controlled trials are warranted to validate our findings.

Rituximab for the treatment of idiopathic membranous nephropathy with nephrotic syndrome: a systematic review and meta-analysis

This meta-analysis comprehensively investigated the efficacy and safety of rituximab (RTX) in patients with idiopathic membranous nephropathy (IMN). We searched the MEDLINE, EMBASE and Cochrane Registry of Controlled Trials databases from January 2000 to January 2020. Studies evaluating the efficacy and safety of RTX in the treatment of IMN with nephrotic syndrome (NS) were included. Nine studies (total of 357 patients) were included in the meta-analysis. The pooled complete response and overall response (OR) rates at 12 months were 13.2% [95% con fidence interval (CI), 0.09–0.18] and 60% (95% CI, 0.48–0.72), and those at 24 months were 27.8% (95% CI, 0.22–0.34) and 66% (95% CI, 0.6–0.72), respectively. The pooled OR rates for the low-, standard-, and high-dose groups were 39.3%, 64%, and 60%, respectively, and those for the first-line and second-line groups were 58% and 54%, respectively. Treatment of IMN with RTX has comparable efficacy to other immunosuppressive treatments (ISTs). RTX has the advantages of no requirement for steroids and lower rates adverse event and relapse rates. Patients who relapse or are resistant to other IST agents also respond to RTX. RTX-based regimens and other B-cell-targeted therapies may represent the future of IMN therapy.

Upfront or add-on combination therapeutic strategy exploration in unresectable hepatocellular carcinoma using sorafenib plus sintilimab: A retrospective analysis of real-world evidence.

e16135 Background: Recently, tyrosine kinase inhibitor plus PD-1 inhibitor regimen has shown promising effects on hepatocellular carcinoma (HCC). So far, no study explored the effectiveness of upfront versus add-on combination therapy in patients with systemic treatment-naïve and treatment-experienced HCCThis study aimed to explore the effectiveness and safety of sintilimab combined sorafenib in patients with untreated or sorafenib monotherapy-refractory unresectable HCC. Methods: In this retrospective study, unresectable HCC patients received sintilimab plus sorafenib from January 2018 to December 2020 were enrolled. According to the prior treatment, patients were grouped as first-line and second-line (received sorafenib combined sintilimab after progression on sorafenib alone). Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), safety, and the change of Child-Pugh score from baseline to progression were recorded. The PFS was defined as the time from first dosing of sintilimab until disease progressive or death. Results: A total of 31 patients were reviewed, including 19 patients in first-line group and 12 patients in second-line group. There were two patients with Barcelona Clinic Liver Cancer (BCLC) stage B and 17 patients with BCLC stage C in first-line group, and one patient with BCLC stage A and 11 patients with BCLC stage C in second-line group, respectively. The ORR and DCR were 27.8% and 77.8% in first-line group, and 16.7% and 75.0% in second-line group, respectively. Fourteen cases in first-line group and 10 cases in second-line group showed PD during the follow-up. The 6-month PFS rate of first-line group and second-line group were 47.1% and 64.8%, respectively. Thirteen and 9 patients experienced AE in two groups. Four and 2 grade 3 AEs occurred in two groups, respectively. The most frequency AE were hand-foot-skin reaction in both group (58.0% and 50.0%, respectively). One patient discontinued sintilimab due to AE in second-line group. Among PD patients, the Child-Pugh score improved in 2 cases, maintained in 5 cases, and deteriorated in 7 cases in the first-line group; and improved in 3 cases, miantained in 3 cases, and deteriorated in 4 cases in the second-line group. Conclusions: Sorafenib plus sintilimab showed potential anti-tumor effect and tolerance on unresectable HCC, either as first-line therapy or after progression with sorafenib monotherapy. Outcomes.[Table: see text]