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Background Current treatment options for human epidermal growth factor receptor 2 (HER2)‐overexpressing gastric cancer at third‐line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in‐situ hybridization‐negative patients. Here, we report the efficacy and safety of a novel anti‐HER2 antibody RC48 for patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer. Methods Patients with HER2‐overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second‐line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. Results Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%‐33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7‐4.9 months) and 7.9 months (95% CI: 6.7‐9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48‐related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48‐related. Conclusions RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy. RC48 is safe and efficacious for HER2‐overexpressing gastric cancer patients. Patients received trastuzumab showed similar efficacy with trastuzumab‐naïve patients. HER2 status doesn't have significant effect on clinical outcomes.

Background Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand‐foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose‐escalation strategy for elderly refractory mCRC patients. Patients and Methods This open‐label, single‐arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28‐day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug‐related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression‐free survival (PFS). Results A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7–4.9), and the median OS was 7.6 months (95% CI, 6.5–8.7). Treatment‐related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). Conclusion Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose‐escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Introduction ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second‐line protease inhibitor (PI)‐based antiretroviral therapy (ART) from 10 low‐ and middle‐income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third‐line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV‐1 RNA ≤200 copies/ml. We report here long‐term outcomes over 144 weeks. Methods Study participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. “Extended Follow‐up” of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow‐up of ≥144 weeks), with HIV‐1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow‐up. Proportion of participants with HIV‐1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow‐up; mean CD4 count changes were estimated using loess regression. Results and Discussion Of 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm3, and HIV‐1 RNA was 4.6 log10 copies/ml. Median follow‐up was 168 weeks (IQR: 156–204); 15 (6%) participants were lost to follow‐up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV‐1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74–85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm3 (95% CI 247–283). Conclusions Third‐line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second‐line PI‐based ART prior to the availability of dolutegravir.

Background Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin‐dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. Methods This Phase 2 open‐label study enrolled patients with metastatic PDAC who progressed after 1–2 prior therapies. Patients were enrolled in a safety lead‐in (abemaciclib plus galunisertib) followed by a 2‐stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib‐containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression‐free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. Results One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4–1.8), 1.8 months (95% CI: 1.3–1.9), and 3.3 months (95% CI: 1.1–5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. Conclusion In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC. Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This phase 2 randomized study for refractory metastatic PDAC patients showed that the CDK4/6 inhibitor abemaciclib, alone or in combination with the PI3K/mTOR LY3023414, does not improve disease control or progression‐free survival compared to standard chemotherapy.

Background Patients with small‐cell lung cancer (SCLC) primarily present with extensive stage (ES) disease and poor 5‐year survival. There are few treatment options and limited data on outcomes in third‐line (3L) ES SCLC to quantify unmet medical needs. This chart review evaluated real‐world (RW) clinical outcomes and treatment patterns in these patients. Methods This retrospective study using electronic medical records included adult patients with ES SCLC (≥ 2 claims for metastasized lung cancer) who received ≥ 3 lines of therapy (LOT) at Cancer Treatment Centers of America (now City of Hope). Patients with other/multiple primary malignancies, non‐SCLC histology, or treated through a clinical trial were excluded. Clinical outcomes included RW physician‐reported response rates, duration of response (DOR), duration of clinical benefit (DoCB), overall survival (OS), and progression‐free survival (PFS), stratified by platinum sensitivity and Eastern Cooperative Oncology Group performance status (ECOG‐PS). Time‐to‐event outcomes were estimated via Kaplan–Meier. Treatment patterns were assessed, including the sequence of regimens by LOT and first‐line (1L) platinum sensitivity status. Results Among 113 eligible patients (median age 58 years), 54% were female, and 46% had a chemotherapy‐free interval after 1L of < 90 days. Tumor shrinkage, complete response, and stable disease were reported in 19%, 1%, and 13% of patients at 3L, respectively. The median DOR, DoCB, OS, and PFS were 2.8, 2.5, 5.8, and 2.4 months in 3L, respectively. Platinum‐resistant versus sensitive patients in 1L had shorter time‐to‐event outcomes. Clinical outcomes were similar regardless of ECOG‐PS status. Platinum‐based chemotherapy rates decreased from 94% and 93% in 1L to 17% and 16% in 3L in platinum‐sensitive and resistant patients, respectively. Conclusion These RW findings validate 3L results from clinical trials, demonstrating the limited clinical benefits with current therapies in 3L ES SCLC, and highlighting the urgent need for novel therapies that improve outcomes in this difficult‐to‐treat patient population.

Abstract Background Advanced pancreatic ductal adenocarcinoma (aPDAC) has a poor prognosis with median overall survival (OS) of about 12 months. It is therefore important to explore factors that predict the efficacy of third-line chemotherapy (L3) to identify patients who may benefit from this controversial treatment. Methods We conducted a multicenter retrospective cohort-based study of 202 French patients treated for aPDAC who received at least three treatment lines from January 2011 to March 2022. We used penalized Cox regressions to predict progression-free survival (PFS) and OS in patients on L3. Results Median age at the start of L3 was 64.3 years old and 63.5% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 or 1. The most frequent regimens for L3 were FOLFIRI (25.2% of patients). Median PFS was 2.2 months, while median OS was 4.2 months. In multivariate models, we identified the following predictors of both PFS and OS: age, sex, surgery for the primary tumor, FOLFIRINOX as the first-line therapy, duration of first and second-line treatments, and for L3: ECOG-PS level, peritoneum, liver and/or lung metastasis and depletion of therapeutic resources. The model incorporating these factors provided acceptable discrimination between event and event-free patients at 6 months post-L3 (area under the ROC curve of 0.83 for PFS and 0.73 for OS). Conclusion The characteristics of patients and their aPDAC are readily available in clinical practice and were able to predict survival with L3. The online calculator we propose here could help physicians determine whether L3 chemotherapy would be beneficial.

Autoimmune encephalitis (AE) is an immune-mediated disease involving the central nervous system, usually caused by antigen-antibody reactions. With the advent of autoantibody-associated diseases, AE has become a hot research frontier in neuroimmunology. The first-line conventional treatments of autoimmune encephalitis consist of steroids, intravenous immunoglobulin (IVIG), plasma exchange (PLEX), and second-line therapy includes rituximab. Despite considerable research and expanding clinical experience, current treatments are still ineffective for a significant number of patients. Although there is no clear consensus, clinical trial evidence limited, and the level of evidence for some of the drugs based on single reports, third-line therapy is a viable alternative for refractory encephalitis patients. With the current rapid research progress, a breakthrough in the treatment of AE is critical. This article aims to review the third-line therapy for refractory AE

Background Anlotinib showed significant survival benefits in advanced non‐small cell lung cancer (NSCLC) patients as a third‐ or further‐line treatment in the ALTER0303 trial. We aimed to evaluate the efficacy of anlotinib in patients with different histologies. Methods The ALTER0303 trial was a randomized, open‐label, phase 3 study of anlotinib in NSCLC patients previously treated with at least two lines of chemotherapy or a tyrosine kinase inhibitor (TKI) in 31 centers in China. Patients were randomly assigned at a 2:1 ratio to receive anlotinib (12 mg QD from days 1 to 14 of a 21‐day cycle) or placebo until progression or intolerable toxicity. The primary endpoint was overall survival (OS). We assessed the efficacy of anlotinib in histological subgroups in the full analysis set. Results In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. In the ACC subgroup, the median OS time was significantly improved with anlotinib compared with placebo (9.6 months vs 6.9 months, P = .0051), as was the median progression‐free survival (PFS) time (5.5 months vs 1.4 months, P < .0001). In the SCC subgroup, the median OS time was 10.7 months in the anlotinib group and 6.5 months in the placebo group (P = .2570), and the median PFS time was 4.8 months and 2.7 months (P = .0004), respectively. The common adverse events observed in the SCC and ACC subgroups were similar. Conclusions Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients. In this study, we evaluated the efficacy of anlotinib as third‐ or further‐line treatment for patient with different histological types of NSCLC. In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients.

Background The third-line treatment options recommended by guidelines for metastatic colorectal cancer (mCRC) are limited with unsatisfactory efficacy. Immune checkpoint inhibitor (ICI)-based strategies have been extensively explored for microsatellite stable (MSS) mCRC at third-line and above settings. This study aimed to evaluate the efficacy and safety of ICI versus non-ICI-based treatments for MSS mCRC patients in third-line setting. Methods Electronic medical records of MSS mCRC patients who received at least third-line therapies at Renmin Hospital of Wuhan University between September 2019 and April 2024 were reviewed retrospectively. Propensity score matching (PSM) was used to balance potential confounding factors. The primary outcomes of interest were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (TRAEs). Results Of 243 eligible patients, 93 received third-line ICI therapy and 150 treated with non-ICI therapy. The ORR were 12.9% vs 9.3% and DCR were 80.6% vs 72.0%, respectively. After PSM, an improved median PFS was exhibited in the ICI cohort (5.0 vs 3.6 months; HR = 0.55; 95% CI, 0.39–0.78; P  < 0.001), with a directional improvement of OS (13.8 vs 12.4 months; HR = 0.70; 95% CI, 0.47–1.05; P  = 0.086). In addition, a more significant survival benefit was found in the triplet regimen of ICI, chemotherapy and target therapy, with a median PFS of 8.2 months and OS of 20.2 months. Patients > 60 years of age, male, with liver metastasis, prior anti-VEGF(R) therapy, and wild-type RAS/BRAF could obtain PFS benefit from third-line ICI over non-ICI treatment. Thirty-six (38.7%) patients developed at least once cross-line immunotherapy in ICI cohort, resulting a directional OS improvement. Grade ≥ 3 AEs occurred in 39.8% and 43.3% of patients in each cohort. Immune-related AEs (irAEs) was 38.7%, and grade ≥ 3 irAEs was 14.0% in ICI cohort. Conclusion ICI is a beneficial addition to third-line treatment for some MSS mCRC patients, providing improved survival benefit and controllable safety.