Second-line Treatment Research Articles

Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer

Human epidermal growth factor 2 (HER2)-positive breast cancer (BC) represents nearly 20% of all breast tumors. Historically, these patients had a high rate of relapse and dismal prognosis. The advent of HER2-targeting monoclonal antibodies such as trastuzumab followed by pertuzumab had improved the prognosis of HER2-positive metastatic BC. More recently, antibody-drug conjugates (ADCs) are now reshaping the treatment paradigm of solid tumors, especially breast cancer. Tratsuzumab emtansine (T-DM1) was one of the first ADC developed in oncology and was approved for the management of HER2-positive metastatic BC. In a head-to-head comparison, trastuzumab deruxtecan (T-DXd) defeated T-DM1 as a second-line treatment. The efficacy of ADCs is counterbalanced by the appearance of acquired resistance to these agents. In this paper, we summarize the mechanisms of action and resistance of T-DM1 and T-DXd, as well as their clinical efficacy. Additionally, we also discuss potential strategies for addressing resistance to ADC.

The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Zuberitamab, an innovative anti-CD20 monoclonal antibody, for patients with primary immune thrombocytopenia in China: a randomized, double-blind, placebo-controlled, phase 2 study

Primary immune thrombocytopenia (ITP) is an autoimmune disease, and rituximab (RTX) induces long-term effect as second-line treatments. Zuberitamab is an innovative anti-CD20 monoclonal antibody, which was first developed in China and launched in diffuse large B lymphoma. This study aimed to investigate the safety, efficacy, and anticipated therapeutic dose of zuberitamab in Chinese ITP patients. This randomised, double-blind, placebo-controlled, phase 2 study was conducted at 26 hospitals in China. Eligible patients were aged 18-70 years, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous treatment and had a pre-treatment platelet count of <30×109/L. Patients randomly received zuberitamab in a dose escalation (100/300/600mg) or placebo once-weekly for 4 weeks and followed up to 24 weeks. The primary endpoint is the proportion of patients with a platelet count ≥50×109/L at week 8. Secondary endpoints include the proportion of patients with platelet counts ≥50×109/L or ≥100×109/L at least once within week 12/24, the proportion of patients experiencing platelets increased twice more than baseline as well as ≥30×109/L at least once during the treatment. Adverse events, pharmacokinetic, B cell depletion and immunogenicity were also assessed. This study is registered with https://www.chictr.org.cn/as ChiCTR2100050513. From October 2021 to March 2023, 50 patients were screened for eligibility, of whom 32 patients were enrolled and randomly assigned to placebo (n=4), zuberitamab 100mg (n=10), 300mg (n=8) and 600mg (n=10) groups. The primary endpoint (PLT ≥50×109/L at week 8) was achieved by 40% of patients in the 100mg group, while none in the other groups. Within 12 weeks, the proportions of patients in each treatment group achieving at least one instance of platelet count ≥50×109/L or ≥100×109/L or an increase twice more than baseline as well as ≥30×109/L were (70%, 38%, 50%), (60%, 13%, 30%), and (80%, 50%, 70%) in zuberitamab 100/300/600mg groups, respectively. By week 24, the proportions of patients achieving these secondary endpoints remained relatively stable or showed a mild increase of around 10%. The anticipated therapeutic dose of zuberitamab was 100mg. The plasma concentration of zuberitamab showed an increasing trend with dose (100mg-600mg) and linear pharmacokinetic behavior. CD19+ B cells and CD20+ B lymphocytes rapidly declined to 0% within one week and consistently maintained reduced levels throughout the entire treatment phase in three groups. Adverse events occurred in all patients with most of them were mild to moderate, no severe infections occurred. A slight decrease in immunoglobulins was observed in the 600mg group, but gradually recovered at week 20. Three patients (2 in 100mg and 1 in 600mg group) were tested positive for anti-zuberitamab antibodies. We also observed that women, disease duration <12 months, and MAIPA+patients may have higher response rates. This study preliminarily confirmed that 100mg zuberitamab was safe and effective in treating ITP and was recommended to support further investigation. National Natural Science Foundation of China and Zhejiang Bioray Biopharmaceutical Co. Ltd.

Beyond Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer: New Frontiers, New Challenges.

Chemoimmunotherapy is currently the preferred first-line treatment option for the majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most of these patients, however, will experience disease progression within the first year after treatment initiation and both patients and their physicians will be confronted with the dilemma of the optimal second-line treatment. Identification of molecular targets, such as KRASG12C, BRAFV600X, METexon14, and human epidermal growth factor receptor 2 mutations, and RET rearrangements offer therapeutic opportunities in pretreated patients with corresponding alterations. For those tumors that do not harbor oncogenic drivers, second-line treatment with docetaxel remains the current standard of care despite modest efficacy. Strategies to challenge docetaxel include the combination of immune checkpoint inhibitors (ICIs) with tyrosine inhibitors of multiple kinases or with DNA damage response inhibitors, antibody-drug conjugates, and locoregional treatments for oligoprogressive disease. Next-generation immunotherapy strategies, such as T-cell engagers, immune-mobilizing monoclonal T-cell receptors, chimeric antigen receptor cell therapy, tumor infiltrating lymphocytes, and T-cell receptor cell therapy are being currently investigated in the quest to reverse resistance to ICIs. Importantly, the advent of these new agents heralds a novel spectrum of toxicities that require both the physician's and the patient's education. Herein, we review current and future strategies aiming to outperform docetaxel after chemoimmunotherapy failure, and we provide practical information on how to best communicate to our patients the unique toxicity aspects associated with immunotherapy.

Cost-effectiveness analysis of tislelizumab vs. camrelizumab for the treatment of second-line locally advanced or metastatic esophageal squamous cell carcinoma

BackgroundEsophageal carcinoma is a type of cancer that occurs in the esophagus. For patients with locally advanced or metastatic esophageal squamous cell carcinoma who have either experienced disease progression following first-line standard chemotherapy or are intolerant to it, the prognosis is typically poor. Additionally, these patients often bear a substantial economic burden during the course of their treatment. Tislelizumab is a selective PD-1 inhibitor with efficacy proven in locally advanced or metastatic esophageal squamous cell carcinoma. The study aims to evaluate the cost-effectiveness of tislelizumab versus camrelizumab as the second-line treatment in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients in China.MethodsFrom the perspective of China’s healthcare system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime horizon. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from RATIONALE 302 trial and the published ESCORT study due to the lack of head-to-head clinical trials. Only direct medical costs were included. Costs and utility values were derived from local charges, the published literature, and related databases. Sensitivity analyses and a scenario analysis were also performed to verify the robustness of the model results.ResultsCompared with camrelizumab monotherapy, tislelizumab monotherapy incurred a lower lifetime cost ($8,346 vs. $8,851) and yielded higher quality-adjusted life-years (QALYs) (0.87 vs. 0.63), which resulted in an incremental cost-effectiveness ratio (ICER) of -$2,051/QALY. Tislelizumab monotherapy is a dominant option over camrelizumab monotherapy in China. The three primary parameters upon which this result was most sensitive were the unit cost of camrelizumab, the unit cost of tislelizumab, and the duration of reactive cutaneous capillary endothelial proliferation (RCCEP). According to the probabilistic sensitivity analysis (PSA), tislelizumab monotherapy was 100% cost-effective when the WTP was 1–3 times GDP per capita in China($11,207/QALY∼$33,621/QALY). Scenario analysis showed that the result was consistent.ConclusionTislelizumab monotherapy is a dominant option compared with camrelizumab monotherapy as the second-line treatment for locally advanced or metastatic ESCC in China.

Evaluation of the efficacy and safety of nivolumab in the second- or later-line treatment of patients with locally advanced/metastatic non-small cell lung cancer in Türkiye: a retrospective multicenter non-interventional registry study.

To evaluate the efficacy and safety of nivolumab in the second-line (2L) or later-line (LL) treatment of patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) in real-life setting in Türkiye. This study was designed as a national, multi-center, retrospective study. The study population was evaluated in two groups for the line of nivolumab therapy: those receiving nivolumab in the 2L (Group 2L) and third-line (3L) or LL (Group 3L/LL). Efficacy was evaluated based on one-year overall survival (OS) and progression-free survival (PFS). Safety was evaluated based on treatment-related adverse events (AEs) and nivolumab discontinuation rate. Of 244 patients, 52.9% were in Group 2L and 47.1% were in Group 3L/LL. Demographic and clinical characteristics did not differ between the groups. In Group 2L and Group 3L/LL, one-year OS and PFS rates were 60.8% and 61.4% (p = 0.592) and 31.2% and 21.3% (p = 0.078), respectively. The objective response rate (ORR) was 34.7% in Group 2L and 27.3% in Group 3L/LL (p = 0.262). The percentage of patients reporting at least one AE in Groups 2L and 3L/LL was 34.9% and 43.5%, respectively (p = 0.169). Fatigue was the most common (16.4%) treatment-related AE in each group. The groups were comparable regarding the AE frequency. Nivolumab was discontinued in 61 patients in Group 2L and 53 patients in Group 3L/LL, with the most common reason being disease progression (57.4% and 66.0%, respectively). Nivolumab is safe and effective in the 2L or 3L/LL treatment of locally advanced/metastatic NSCLC and associated with acceptable AEs in real-life setting.

Comparing the effectiveness and cost-effectiveness of sulfonylureas and newer diabetes drugs as second-line therapy for patients with type 2 diabetes

IntroductionWe aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides...

Real-world study of lazertinib as second-line or greater treatment in advanced non-small cell lung cancer.

Lazertinib is an oral, third-generation EGFR-TKI, which specifically targets the EGFR T790M mutation along with activating mutations Ex19del and L858R. More real-world data are needed to evaluate its efficacy and safety in treating locally advanced and metastatic non-small cell lung cancer (NSCLC) following prior EGFR TKI treatment. This multicenter retrospective study was conducted at seven university hospitals affiliated to the Catholic Medical Center (CMC) in Korea. A clinical data warehouse (CDW) platform was used to access and extract information. A total of 48 patients were assessed. The majority were female (75%) and diagnosed with adenocarcinoma (95.8%). All patients had the EGFR mutation at diagnosis, 27 (56.3%) had the exon 19 deletion, 20 (41.7%) had the L858R mutation, and one (2.0%) had the exon 18 mutation. The median progression-free survival (PFS) was 15.4 months. At 6, 12, and 18 months, PFS rates were 79.1%, 53.6%, and 27.3%, respectively. When PFS was analyzed by prior TKI duration (<18 months vs. >18 months), significant differences were noted at the 6 and 9-month mark (p = 0.013 and p = 0.010, respectively). In multivariate analysis for PFS, only prior TKI duration and ECOG score showed statistical significance (p = 0.026 and p = 0.049, respectively). In the multivariate analysis for OS, ECOG score showed statistical significance (p = 0.006). Among 48 patients, 34 (70.8%) experienced adverse events (AEs) related to lazertinib. The most frequent AEs were skin reaction (29.8%), diarrhea (21.3%), and peripheral neuropathy (20.8%). The results suggest that lazertinib is effective in second or more line settings, with tolerable safety profile. More patient data are necessary to find possible prognostic markers associated with patient outcome.

Ruxolitinib in steroid-refractory acute graft-vs-host disease: Japanese subgroup analysis of the randomized REACH2 trial.

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

The efficacy and safety of apatinib combined with S-1 for advanced gastric cancer: A systematic review and meta-analysis.

Advanced gastric cancer (AGC) that does not respond to first-line therapy poses a challenge to clinical management. The objective of this study was to compare the efficacy and safety of apatinib combined with S-1 in second-line and above treatment of AGC. Cochrane Library, Science Direct, EMBASE, PubMed, and CNKI were searched for randomized controlled trial until August 2023. Only patients who met "Standardized Diagnosis and Treatment Guide for Gastric Cancer" were included in the study. The accurate data and distinguishing between follow-up time and drug dose were extracted to reduce heterogeneity and the risk of bias of the included trials was evaluated according to the Cochrane Handbook. Finally, the survival benefit of the treatment was evaluated based on clinical response rate, survival period, biochemical index, and adverse event occurrence in the trial. The meta-analysis included 29 randomized controlled trials involving 2149 participants. Statistically significant increases in clinical effective rate (odds ratios = 2.61, 95% confidence interval [2.13-3.20], P < .00001) and disease control rate (odds ratios = 3.16, 95% confidence interval [2.54-3.94], P < .00001) were found when apatinib combined with S-1, and also had obvious advantages in reducing tumor markers and regulating immune factors. In addition, apatinib combined with S-1 significantly increased the risk of hypertension but reduced damage to liver function, while the improvement of other adverse events was not pronounced. Apatinib combined with S-1 is more effective and safe for second-line and above treatment of AGC. This study minimized the conclusion bias caused by the basic data sources, but more high-quality studies are still needed to validate these conclusions.

Personality and quality-of-life improvement after apomorphine infusion in Parkinson’s disease

Abstract People with Parkinson’s disease with motor fluctuations can be treated by Continuous Subcutaneous Apomorphine Infusion (CSAI) to reduce their symptoms. Nonetheless, factors are lacking to predict patients’ quality-of-life amelioration after CSAI. This pilot study aimed to evaluate associations between personality dimensions and quality-of-life improvement after six months of CSAI. Thirty-nine people with Parkinson’s disease awaiting CSAI were included. Linear regression models between “Temperament and Character Inventory” personality dimensions at baseline and percentage of change in PDQ-39 (Parkinson’s Disease Questionnaire-39) scores after six months of CSAI were realized (n = 35). Temperament and Character Inventory was also compared between patients awaiting CSAI and patients awaiting deep brain stimulation of the sub-thalamic nucleus (n = 39 from the PREDI-STIM study). Higher Reward Dependence scores were associated with a better quality-of-life outcome after six months of CSAI, while Self-Directedness scores were associated with a better quality of life before CSAI (as opposed to Harm Avoidance, Reward Dependence, and Self-Transcendence scores associated with a worse quality of life). Moreover, people with Parkinson’s disease awaiting deep brain stimulation of the sub-thalamic nucleus had similar Temperament and Character Inventory dimensions compared to patients awaiting CSAI. People with Parkinson’s disease with higher Reward Dependence scores at baseline had the best quality-of-life improvement after six months of CSAI. This finding could be used to better prepare and accompany people with Parkinson’s disease during CSAI establishment. Moreover, this result could serve as an orientation factor to second-line treatments.

Real-world treatment patterns and quality of life among patients with locally advanced or metastatic urothelial carcinoma living in Saudi Arabia, South Korea, Taiwan, and Turkey.

To evaluate demographic and clinical characteristics, treatment patterns, and quality of life in patients with locally advanced or metastatic urothelial carcinoma in Asia. Data were drawn from the Adelphi Real World Metastatic Urothelial Carcinoma Disease Specific Programme™, a cross-sectional survey of medical oncologists/urologists and their adult patients in Saudi Arabia, South Korea, Taiwan, and Turkey. Exploratory patient-reported outcomes included the EQ-5D visual analog scale, European Organisation for Research and Treatment of Cancer Quality of Life of Patient Questionnaire global health, and Brief Pain Inventory. Analyses were descriptive. Overall, 175 physicians reported data for 988 patients. Mean (standard deviation) patient age was 66.3 (10.8) years, 77% were men, and 82% had bladder tumors at diagnosis. Of patients receiving first- (n = 988), second- (n = 290), and third-line (n = 87) treatments, 81%, 35%, and 59% received chemotherapy, respectively, and 17%, 63%, and 34% received programmed cell death protein 1/ligand 1 inhibitors, respectively. Patient-reported (n = 319) mean (standard deviation) EQ-5D visual analog scale score was 51.8 (15.6), European Organisation for Research and Treatment of Cancer Quality of Life of Patient Questionnaire global health status score was 44.6 (19.9), and Brief Pain Inventory score was 6.5 (1.9; n = 315). The most common first- and second-line treatments for locally advanced or metastatic urothelial carcinoma were chemotherapy and programmed cell death protein 1/ligand inhibitors, respectively. At third line, 10% of patients received best supportive care alone, underscoring an unmet need for effective third-line treatment options. Patients in all regions reported quality-of-life impairment.

Prospective, Observational Study of Aflibercept Use in Combination with FOLFIRI in Patients with Metastatic Colorectal Cancer: A Real-World Effectiveness Study

Background: This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. Methods: Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. Results: A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9–9.9] and 27.0 months [95% CI, 23.9–30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). Conclusions: The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed.

Real-world efficacy and safety of capecitabine with oxaliplatin in patients with advanced adenocarcinoma of the ampulla of Vater

BackgroundAdenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic subtypes. Its rarity and diversity pose challenges in treatment decision-making for patients with advanced AoV carcinoma. This study investigated the efficacy and safety of the combined regimen of capecitabine and oxaliplatin (CAPOX) in a real-world clinical setting.MethodsThis investigation encompassed patients with advanced AoV carcinoma who underwent CAPOX treatment. Histologic phenotypes were identified through a combination of histopathological analysis and protein expression markers, including MUC1, CDX2, CK20, and MUC2. The correlation between histopathological determinants and survival outcomes was explored, in addition to an evaluation of the safety profile of CAPOX therapy.ResultsFrom January 2010 to June 2023, 42 patients received CAPOX. Of these, 14 patients (33.3%) had not received any prior palliative chemotherapy, while 28 patients (66.7%) had undergone one prior line of chemotherapy. At a median follow up of 9.0 months, the median progression-free survival (PFS) was 4.38 months (95% CI, 2.78–5.69) and the median overall survival (OS) was 9.57 months (95% CI 7.56–11.6). The objective response and disease control rates were 38.1% and 61.9%, respectively. Patients who received CAPOX as a second-line treatment had poorer PFS (HR = 2.62; 95% CI, 1.49–4.90, p = 0.003) and OS (HR = 2.82, 95% CI, 1.47–5.38, p = 0.001) compared to those who received CAPOX as a first-line chemotherapy. There were no statistically significant differences in PFS (p = 0.185) and OS (p = 0.097) between groups based on histologic subtypes. Neutropenia (14.3%) emerged as the predominant grade 3–4 toxicity. Notably, treatment cessation occurred in select instances owing to grade 3 fatigue (9.5%) and peripheral neuropathy (9.5%).ConclusionsThis study confirmed the therapeutic efficacy and safety of CAPOX in a real-world setting, consistent with prior phase II trial results. While CAPOX proved feasible for advanced AoV carcinoma regardless of histologic subtype, its reduced effectiveness in second-line settings necessitates further research to determine its optimal palliative use.

#2101 Beyond corticosteroids: rituximab in managing minimal change disease and glucocorticoid-related toxicity

Abstract Background and Aims Minimal Change Disease (MCD) is the primary cause of Nephrotic Syndrome in children, accounting for 10 to 20% of cases in adults. Glucocorticoids (GC) remain the cornerstone of treatment. Despite a positive response in the majority of patients, up to 25% experience frequent relapses, and up to 30% are GC-dependent, exposing them to significant GC-related toxicity. Rituximab has been increasingly used in these patients, although 2021 KDIGO guidelines still points to cyclophosphamide as the preferred second-line therapy. This study aims to describe a single-centre experience with RTX, examining its effectiveness and assessing its potential to reduce GC exposure. Method A retrospective cohort study was conducted on 19 patients with MCD who were considered for RTX at adult age at a tertiary hospital centre between 2015 and 2023. Patients who refused treatment, those with MCD associated with other glomerular diseases, and those with less than 6 months of follow-up post-RTX were excluded from the study. Results Twelve patients met the inclusion criteria, including 5 diagnosed before the age of 18. The mean age at RTX initiation was 38.8 ± 14.8 years, with 75% being male. The median MCD duration pre-RTX was 140.5 [18.8–353.5] months, and the median follow-up post-RTX was 18.0 [12.5–41] months. All patients had preserved renal function and exhibited GC-dependency and/or frequent relapses, with 8 patients having received prior cyclophosphamide and/or cyclosporine A (CsA) treatment. At RTX initiation, all patients were on GC therapy (median 11.1 [10–50] mg/day), with 4 also on CsA. 10 patients were in complete remission, while 2 were in a relapse phase, subsequently achieving complete remission. Various induction regimens were employed: 6 patients received 1000 mg of RTX twice within 2 weeks, 1 received a single dose of 1000 mg, and 5 received a single dose of 500 mg. Out of the 12 patients, 5 did not receive RTX maintenance administrations, while 6 received 500 mg of RTX every 6 to 9 months and 1 patient received 1000 mg every 6 months. Only one adverse event was reported, one uncomplicated upper respiratory tract infection. Regardless of the induction regimen, all patients maintained a sustained response with complete remission for the following 6 months. All the 7 patients who underwent RTX maintenance did not experience disease relapse, although 2 continued GC therapy (one due to an associated autoimmune disease). Among the 5 patients who did not undergo RTX maintenance, 3 maintained complete remission throughout the follow-up, with a mean time free from any immunosuppression of 14.8 ± 10.6 months. The other 2 patients relapsed at a mean time of 27.5 ± 0.7 months. After relapse, 1 patient resumed GC therapy, and both started RTX maintenance with 500 mg every 6 to 9 months, subsequently achieving and maintaining complete remission. Among the 12 patients, 9 discontinued GC (1 continued CsA) after an average of 5.9 ± 4.2 months post-RTX, with a mean GC-free period of 16.6 ± 13.2 months during the follow-up period. Conclusion RTX proved to be safe and effective for steroid-dependent and/or frequently relapsing MCD, even with a low induction single dose of 500 mg. This low induction regimen may be an effective and potentially preferable option to minimize toxicity. RTX can significantly reduce relapse rate and steroid dose, avoiding complications associated with extended and high-dose GC administration. Notably, this outcome was not achieved previously with cyclophosphamide or CsA. RTX maintenance therapy may not be universally required for all patients with MCD, since a long period without relapse can be observed after induction therapy. Considering the current absence of a marker for disease activity, it should be taken into account individual patient characteristics and disease severity, particularly previous relapses after RTX induction. Considering the RTX effectiveness, ability to extend remission, safety, and GC sparing ability, it should be seriously considered as the preferred second-line treatment.

#487 Treating chronic kidney disease in Danish primary care: results from the observational ATLAS study

Abstract Background and Aims Little is known about the clinical characteristics and medical treatment of individuals with chronic Kidney Disease (CKD) in primary care clinics, including uptake of cardio-renoprotective treatments like renin-angiotensin-system inhibitors (RASi) and sodium glucose co-transporter 2 inhibitors (SGLT2i). Therefore, the aim of this study were to describe the clinical characteristics, comorbidity, and medical treatment in the primary care population with decreased estimated glomerular filtration rate (eGFR) and albuminuria. Additionally, to examine the awareness and habits of primary care physicians (PCP) in regard to CKD and treatment patterns in this high-risk patient population. Method An observational study of current CKD prevalence, treatment patterns and comorbidities in primary care based on patient record data, Data was drawn from 128/211 randomly invited primary care clinics throughout Denmark. A computerized selection identified 12 random individuals with CKD per clinic with ≥2 measurements of eGFR &amp;lt;60 mL/min/1.73 m2 or UACR &amp;gt;30 mg/g within two years. Pre-specified data collected from individual electronic health records included demographics, clinical variables, comorbidities, and relevant prescribed medications. Our analyses was strengthened by 125/128 PCP completing a questionnaire with responses regarding diagnosis, management and treatment of impaired kidney function in a real-world, primary care setting. Results Of the identified CKD study population (N = 1497), 80% had hypertension, 32% diabetes (DM), 13% heart failure (HF), 59% no DM/HF. RASi were prescribed to 65%, statins to 56%, SGTL2is to 14%, and MRAs to 8% of all individuals. Treatment patterns differed between individuals with varying comorbidities, e.g., RASi usage was higher in DM (76%) or HF (74%) vs. no DM/HF (58%), as was statin usage (76% in DM vs. 45% in no DM/HF). SGTL2i usage in CKD without DM/HF was low. Questionnaire results showed that most PCPs identified CKD using threshold eGFR &amp;lt;60 mL/min/1.73 m2 (62%) or UACR &amp;gt;30 mg/g (58%) and 62% reported initiating treatment to retard kidney function decline. 53% of PCPs reported using SGLT2is as second-line treatment for CKD. 38% of PCPs often spoke to patients with an eGFR &amp;lt;60 mL/min/1.73 m2 as having CKD, whilst 38% reported rarely doing so and 19% never did so. The voluntary nature of PCP study participation (accepting an invitation to participate) may have generated bias towards those with an interest in CKD. Conclusion Despite good PCP awareness and wish to use relevant guidelines, a gap exists in implementation of cardio-renoprotective treatment, especially in individuals without DM or HF. Data from both patient files and questionnaires emphasizes a need for clear recommendations to PCPs to optimize early cardio-renal protection in individuals with CKD. Applying the same systematic screening as in individuals with DM to non-diabetic populations could offer a paradigm shift for the identification, diagnosis and monitoring of CKD. Boehringer Ingelheim supported this study, but had no role in the design, analysis or interpretation of the results.

Combining anti-VEGFR and anti-EGFR antibodies: Randomized phase II study of irinotecan and cetuximab with/without ramucirumab in second-line colorectal cancer:(ECOG-ACRIN E7208).

Early studies showed promise of combined anti-EGFR plus anti-VEGF antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab (IC) with or without the anti-VEGFR antibody, ramucirumab (ICR). Patients with one prior regimen including fluoropyrimidine, oxaliplatin and bevacizumab, with KRAS wild-type tumors, were stratified by ECOG PS, time since last chemotherapy and progression on oxaliplatin, to IC (180 and 500 mg/2 q2w), vs modified ICR (mICR) (150 and 400 mg/m2 plus 6 mg/kg respectively). 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months). Of the 102 enrolled, 44 treated with IC and 45 with mICR were evaluable. Median PFS was 6.0 vs 9.2 months respectively (HR 0.75, p = .07, significant by study design for p < .128). Response rate was 23% vs 36% (p = .27) and disease-control rate (DCR) was 52% vs 73% (p = .05). Grade ≥3 toxicity was not equivalent. Overall survival was not significantly different at ∼19 months. Previous phase 3 trials without RAS genotyping, rejected combining anti-EGFR and anti-VEGF drugs. In this randomized multi-center phase 2 study for KRAS wild type CRC (all previously bevacizumab-treated) the addition of ramucirumab, to irinotecan and cetuximab improved PFS and DCR, showing the combination is feasible and effective here. Further phase 3 trials with appropriate patient-selection are required. (NCT01079780).

Compliance with the pregnancy prevention program among women initiating isotretinoin treatment between 2014 and 2021: Anationwide cohort study on the French Health Data System (SNDS).

Despite the French pregnancy prevention program (PPP), a considerable number of pregnancies are potentially exposed to oral isotretinoin. New measures were taken by the French Medicines Agency, including the restriction of initial isotretinoin prescriptions to dermatology specialists in May 2015 and a new information campaign on teratogenicity in January 2019. The aims were to: describe, between 2014 and 2021, compliance with PPP recommendations: isotretinoin use as a second-line treatment, first prescription by a dermatology specialist, monthly prescription renewal and pregnancy testing (PT); assess the effect of the 2015 and 2019 measures on PT compliance; and identify the determinants of PT noncompliance. A retrospective cohort study was conducted among women aged 11-50 years initiating isotretinoin between 2014 and 2021 using the French Health Data System. PT compliance corresponded to pregnancy test completion and specific delays between prescription and dispensation. Time series analyses were performed to evaluate the effect of the 2015 and 2019 measures on PT compliance, and log-binomial and Poisson multivariate regression models were used to identify the determinants of PT noncompliance. Isotretinoin was prescribed as a second-line treatment in 64% of initiations, mainly by dermatology specialists (92%). A new monthly prescription was observed in 98% of dispensations. PT compliance reached 61%, 72% and 25% at initiation, renewals and end of treatment, respectively. The 2015 measure was associated with better PT compliance at initiation and renewals. The 2019 measure had no significant effect on PT compliance at the initiation or end of treatment but was associated with a decrease in PT compliance at renewals. Age, low socioeconomic level, initiation by a nondermatology specialist and during summer were associated with PT noncompliance. Understanding factors associated with PT noncompliance could help to target specific subpopulations of women treated with isotretinoin.

Safety evaluation of lenvatinib treatment after atezolizumab plus bevacizumab therapy for patients with unresectable liver cancer: A comparison of lenvatinib as 1st‑ or 2nd‑line treatment.

Atezolizumab plus bevacizumab (Atez/BV) as first-line therapy and lenvatinib (LEN) as second-line therapy are the recommended treatments for patients with unresectable hepatocellular carcinoma. Adverse immune events caused by immune checkpoint inhibitors (such as Atez) generally only occur several months after administration; therefore, the potential influence of the first-line treatment on second-line treatment is not clear. The present study investigated the safety of second-line LEN treatment (2nd LEN) by comparing the adverse events (AEs) of 2nd LEN after first-line Atez/BV treatment for unresectable liver cancer, with those of first-line LEN treatment (1st LEN). Patients who received Atez/BV as first-line therapy and 2nd LEN, or those who received 1st LEN at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and September 2023 were retrospectively evaluated for treatment duration and AEs. The median treatment duration for patients in the 1st LEN (n=39) and 2nd LEN (n=13) groups was 151.0 days [95% confidence interval (CI) 77-303 days] and 128.5 days (95% CI 68-270 days), respectively (P=0.385). A greater proportion of patients showed elevated aspartate aminotransferase/alanine aminotransferase levels in the 2nd LEN group (76.9%) compared with those in the 1st LEN group (46.2%) (P=0.016). Hypothyroidism was more common in those receiving 2nd LEN (46.2%) than 1st LEN (12.8%) (P=0.016). In addition, grade 1 (three patients) and grade 2 (three patients) hypothyroidism was observed in patients receiving 2nd LEN. For these six patients, during first-line Atez/BV treatment, four patients had grade 0 hypothyroidism and two patients had grade 1 hypothyroidism (P=0.025). In conclusion, patients receiving 2nd LEN after treatment with Atez/BV are at an increased risk of hypothyroidism.

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States

AimTo examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer (ABC).MethodsA retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor–positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes.ResultsWhen diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments.ConclusionClinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.