Targeted Oncology最新文献

Background: Immune-mediated gastroenteritis (IMG) has been commonly managed with proton pump inhibitors (PPIs), though their effectiveness is unclear. Histological analysis has shown depletion of parietal cells in the gastric mucosa during IMG, which inhibits PPI action.

Objective: Extending on a small cohort study, we assessed the role of PPIs, and alternatives such as corticosteroids, for managing IMG.

Patients and methods: This was a retrospective study at a tertiary care cancer center, including patients with malignancy who received an immune-checkpoint inhibitor (ICI) between 2010 and 2024 and developed IMG.

Results: A total of 399 patients were included, of whom 281 (70.4%) received PD-1/PD-L1 inhibitors. Of these, 190 (47.6%) had exclusive IMG, and 69 (36.3%) were treated with PPIs. PPI use did not significantly impact clinical outcomes. In contrast, 156 (39.1%) received corticosteroids, showing improved clinical outcomes (75.8% vs 65%; p = 0.027) and a trend towards faster symptom resolution (41.5 vs 53 days; p = 0.064). Endoscopic remission was achieved in 71.1% of the steroid group and 36.7% of the non-steroid group. ICI discontinuation was more frequent with steroids (73.5% vs 50.7%; p < 0.0001), as was symptom recurrence within 6 months (16.7% vs 3.6%; p < 0.0001). All-cause mortality was higher in the non-steroid group (51.5% vs 41%; p = 0.042), which had a shorter follow-up period (0.7 vs 1.1 years; p = 0.004). Binary logistic regression showed that steroid use (OR 1.7, 95% CI 1.06-2.7; p = 0.027) and ICI discontinuation (OR 1.9, 95% CI 1.1-3.0; p = 0.007) were associated with clinical improvement.

Conclusion: Our findings show faster clinical improvement and higher endoscopic remission rates with steroids, while PPIs demonstrated no significant effectiveness.

Background: Tebentafusp is the first systemic therapy to improve survival outcomes for patients with HLA-A*02:01-positive metastatic uveal melanoma (mUM). However, outside the pivotal study, limited data for tebentafusp are reported in literature.

Objective: To evaluate the efficacy and safety of tebentafusp in patients with human leukocyte antigen (HLA)-A*02:01-positive mUM across cohort studies and clinical trials.

Patients and methods: PubMed, EMBASE, Cochrane, and Web of Science (up to July 2025) were surveyed for studies evaluating tebentafusp in patients with HLA-A*02:01-positive mUM. A meta-analysis using a random-effects model and the inverse variance method was conducted; Kaplan-Meier curves, where available, were used to recreate the time-to-event data. The primary objective was efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The secondary objective was to evaluate all-grade and severe (grade ≥ 3 or higher) adverse events (AEs).

Results: A total of 997 patients from 12 cohorts were included. Using reconstructed time-to-event outcomes from published Kaplan-Meier curves, the estimated median PFS was 3.9 months (95% confidence interval [CI] 3.77-4.92). The median OS was 21.2 months (95% CI 19.2-23.1). When stratified by study design, the median OS was similar between prospective and retrospective studies: 21.2 months (95% CI 19.2-23.8) and 21.1 months (95% CI 18.1-33.6), respectively. Likewise, median progression-free survival (PFS) was comparable between prospective and retrospective studies: 3.8 months (95% CI 3.25-5.5) and 3.9 months (95% CI 3.8-4.9), respectively. The rate of cytokine- and cutaneous-mediated events was 67% (95% CI 45-84; I² = 94.4%) and 64% (95% CI 28-89; I² = 97.3%), respectively. Severe AEs for cytokine-mediated events were 3% (95% CI 1-13; I² = 87.6%), and cutaneous-mediated events were 11% (95% CI 8-14; I² = 0%). The discontinuation rate was 2% (95% CI 1-4; I² = 0%).

Conclusions: Tebentafusp for patients with HLA-A*02:01-positive mUM is associated with improved survival outcomes and manageable toxicity. These findings support tebentafusp as the standard of care for this patient population.

Exploiting DNA damage repair (DDR) vulnerabilities has become a major focus in cancer drug development following the clinical success of poly (ADP-ribose) polymerase (PARP) inhibitors. Beyond PARP, inhibitors of multiple other DDR proteins have progressed from preclinical development to early-phase clinical trials. DNA damage repair inhibitors have shown promise both as a selective therapeutic strategy in genomically selected cancers harbouring specific genetic vulnerabilities, and as a potential treatment approach to overcome innate and acquired PARP inhibitor resistance. This review summarises the most recent DDR inhibitor clinical evidence, focusing on DDR signalling targets; ATR (ataxia telangiectasia and Rad3-related protein serine/threonine kinase), ATM (ataxia telangiectasia mutated kinase), DNA-PK (DNA-dependent protein kinase), CHK1 (checkpoint kinase 1), WEE1 and recently emerging DNA repair targets; RAD51, PolƟ (DNA polymerase theta), WRN (Werner syndrome helicase), USP1 (ubiquitin specific peptidase 1) and PARG (poly(ADP-ribose) glycohydrolase). We highlight both clinical successes and failures of DDR inhibitors as monotherapy or in combination with chemotherapy, PARP and other DDR inhibitors. The challenges that must be addressed to see the true potential of these agents are discussed. Finally, we consider future directions and the necessity for integration of biomarkers and genomic profiling in DDR inhibitor clinical trials to optimally identify patients with tumours genetically vulnerable, and so crucially, take advantage of the selective therapeutic opportunity provided by DDR inhibition.

Introduction: Immune checkpoint inhibitors are a standard first-line treatment for metastatic renal cell carcinoma (RCC), with combination ipilimumab and nivolumab (ipi-nivo) widely recommended. However, real-world data on its use in Australia remain limited.

Objective: To evaluate real-world outcomes of ipi-nivo for metastatic RCC in the Australian healthcare setting.

Methods: We conducted a retrospective cohort study using nationally linked Pharmaceutical Benefits Scheme data and National Death Index records accessed via the Australian Bureau of Statistics DataLab. Patients initiating ipi-nivo for stage IV clear cell RCC between 1 July 2019 and 30 June 2023 were included. Kaplan-Meier analyses and multivariate Cox regression were used to estimate overall survival (OS) and time to treatment discontinuation (TTD). Immune-related adverse events (irAEs) were inferred from incident dispensing of corticosteroids and levothyroxine. Subgroup analyses were performed by age (18-64 versus ≥ 65 years) and sex.

Results: Among 1334 patients, median OS was 30.0 months with 12- and 24-month survival rates of 72.9% (95% confidence interval [CI] 70.5-75.3) and 56.4% (95% CI 53.7-59.2), respectively. Median TTD was 4.9 months, and 38.5% of patients discontinued treatment during the induction phase. Incident corticosteroid and levothyroxine use occurred in 24.2% and 11.2% of patients, respectively. No significant differences in OS, TTD, or irAE proxies were observed by age or sex.

Conclusions: In this national, population-based study, real-world survival outcomes with ipi-nivo for metastatic RCC were shorter than those reported in clinical trials. These findings provide population-level benchmarks from a universal healthcare system and highlight the limitations of applying trial outcomes to unselected real-world populations. By contributing robust, large-scale data from routine practice, this study adds to the global evidence base and supports the integration of real-world data into clinical and policy decisions around immunotherapy.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by plexiform neurofibromas (PNs), which are present in 20-60% of NF1 and may cause potentially life-threatening complications. Complete surgical resection of these PNs is generally not feasible, and regrowth after incomplete surgical resection has been observed. Luvometinib is a novel, oral, highly potent selective MEK1/2 inhibitor that has shown activity in adult NF1-related PN.

Objective: To evaluate the safety and preliminary efficacy of luvometinib in a phase 1 trial in pediatric patients with NF1-related PN.

Patients and methods: This multicenter, single-arm, phase 1 study included pediatric patients (2-18 years old) with unresectable NF1-related PN. Patients received luvometinib orally once daily in 28-day cycles until progression or unacceptable toxicity, using a population pharmacokinetics model-informed approach to identify the starting dose of 4 mg/m². Primary endpoints were dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D). Tumor response was a secondary endpoint.

Results: In total, 19 patients were enrolled; 10 at 4 mg/m² and 9 at 5 mg/m². Median age was 10.0 years (range 5-17). No DLTs were reported. The maximum tolerated dose (MTD) was not reached; the RP2D was 5 mg/m². The most common treatment-related adverse events (TRAEs) were paronychia (52.6%) and mouth ulceration (42.1%), with a single grade ≥ 3 TRAE reported for each: paronychia (5.3%), prolonged QT on electrocardiogram (5.3%), and ingrown nail (5.3%). There was one discontinuation owing to a treatment-related serious AE (SAE) of rhabdomyolysis, the only treatment-related SAE. Within the 5 mg/m² group, six out of nine patients (66.7%) had a confirmed response; within the 4 mg/m² group, none did. Among patients with tumor pain (numerical rating scale [NRS] ≥ 2) at baseline and at least one post-baseline measurement, 2/3 (66.7%) reported an improvement of ≥ 2 points in the 4 mg/m² dose group and 3/3 (100.0%) in the 5 mg/m² dose group.

Conclusions: Luvometinib had a manageable safety profile in pediatric patients with unresectable NF1-related PN. Encouraging preliminary efficacy was observed, particularly among patients receiving the RP2D of 5 mg/m², supporting further investigation of luvometinib in this setting.

Trial registration: ClinicalTrials.gov, NCT04954001 (first posted: 8 July 2021).

The initial approval of palbociclib in 2015 marked a major advancement in the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). As the first-in-class cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, palbociclib introduced a new therapeutic strategy for this disease subtype by targeting the CDK4/6:cyclin-D:Rb pathway to halt cell cycle progression from the G1 to the S phase. The PALOMA clinical trials demonstrated a significant improvement in progression-free survival for palbociclib in combination with endocrine therapy (ET), representing clinically meaningful and consistent progression-free survival benefits across all studies in patients with HR+/HER2- ABC. Although the PALOMA clinical trials did not demonstrate a statistically significant overall survival (OS; secondary endpoint) benefit for palbociclib combined with ET in HR+/HER2- ABC over ET monotherapy, several real-world studies have reported substantial OS improvements in diverse patient populations. Despite the significant improvement in clinical outcomes, there remain challenges, particularly regarding proposed resistance mechanisms such as RB1 loss and CDK2 activation, which may diminish the long-term effectiveness of CDK4/6 inhibitors. Moreover, although the toxicity profiles of CDK4/6 inhibitors, such as the risks of myelosuppression and gastrointestinal side effects, necessitate careful patient monitoring, there is an opportunity to refine their use and explore strategies for broader applicability. For these reasons, further research into next-generation CDK inhibitors and combination therapies are critical and ongoing. This review explores the discovery of CDK inhibitors, the development of palbociclib from preclinical studies to its global approval, and future drug development strategies to overcome resistance and enhance patient outcomes.

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Emerging evidence suggests that it may be associated with increased cardiotoxicity; however, current evidence is conflicting, and a small sample size and a lack of direct comparisons with other EGFR-TKIs limit existing studies.

Objective: We aim to examine the incidence of cardiovascular toxicity with osimertinib compared with other EGFR-TKIs in a real-world setting.

Patients and methods: A retrospective cohort study was conducted via the Trinetx global federated health research platform to compare the incidence of cardiotoxicity between osimertinib and other EGFR-TKIs over a 5-year follow-up. Patients were matched using 1:1 propensity score matching (PSM). Outcomes included cardiomyopathies, arrhythmias, ischemic heart disease (IHD), and heart failure (HF), assessed using ICD-10 codes.

Results: Following PSM, each arm consisted of 7331 patients; the arms were well balanced. Osimertinib was associated with increased risk of cardiomyopathy (2.8% vs 0.8%; HR: 3.143 [95% CI 2.342-4.218]), IHD (8.7% vs 5.5%; HR: 1.432 [95% CI 1.248-1.643]), and HF (6.2% vs 4%; HR: 1.41 [95% CI 1.210-1.644]). A similar incidence of arrhythmia was observed (9% vs 8.5%; HR: 0.938 [95% CI 0.831-1.059]); however, it increased after 3 years. Comparisons with individual EGFR-TKIs showed varying results.

Conclusion: In this large, real-world study, osimertinib was associated with elevated cardiotoxicity risk. These findings underscore the need for serial monitoring of patients receiving osimertinib and for future studies comparing cardioprotective drugs.

Background: Immune checkpoint inhibitors (ICIs) are now standard for various cancers, and preclinical studies suggest beta-blockers (BBs) may boost the efficacy of ICIs. However, prior clinical studies had small sample sizes, requiring large-scale validation.

Objective: We aimed to evaluate the efficacy and safety of combining BBs with ICIs in patients with solid tumors through a systematic review and meta-analysis.

Methods: A systematic search of PubMed/MEDLINE and Embase was conducted for studies on BBs plus ICIs for solid tumors up to July 2024. Outcomes of interest were overall survival, progression-free survival, and adverse events. Hazard ratios with 95% confidence intervals were pooled using a random-effects model meta-analysis, with heterogeneity assessed by I² statistics.

Results: Overall, 12 clinical studies involving 4293 patients with solid tumors were included, with 1463 patients receiving both BBs and ICIs and 2830 patients receiving ICIs alone. The combination of BBs and ICIs was not associated with a longer overall survival (hazard ratio 1.02; 95% confidence interval 0.84-1.23; p = 0.87; I² = 69%) or progression-free survival (hazard ratio 0.98; 95% confidence interval 0.80-1.20; p = 0.81; I² = 71%). Subgroup analyses by cancer types and BB types showed no significant heterogeneity in the hazard ratios for overall survival across different cancer types (I² = 0%, p for heterogeneity = 0.44) and BB types ⁽I² = 0%, p for heterogeneity = 0.67). The combination of BBs plus ICIs did not seem to increase toxicity.

Conclusions: Despite positive preclinical findings, this meta-analysis showed that adding BBs to ICIs was not associated with longer survival. We await the results of ongoing prospective trials assessing this strategy. PROSPERO REGISTRATION: CRD42024574043.