Targeted Oncology最新文献

Background: Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder carcinoma, are aggressive tumors with limited treatment options and poor prognosis. Antibody-drug conjugates (ADCs) targeting membrane proteins, such as claudin-18.2 (CLDN18.2) and trophoblast cell surface antigen 2 (Trop-2), are promising targets for other epithelial cancers. However, their expression patterns and clinical relevance in BTC remain unclear.

Objective: This study aimed to evaluate CLDN18 and Trop-2 expression levels in BTC and their potential as therapeutic targets.

Patients and methods: We retrospectively analyzed 636 patients with BTC who underwent surgical resection at Asan Medical Center between February 1998 and October 2020. Immunohistochemistry was performed using validated antibodies. CLDN18 positivity was defined as membranous staining in ≥ 75% of tumor cells with a moderate-to-strong intensity. Trop-2 expression was quantified by H-score and categorized as low (< 100), medium (100-200), or high (> 200). Associations with clinicopathologic features and survival outcomes were assessed via Kaplan-Meier and Cox regression.

Results: CLDN18 was positive for 5.2% of patients, most frequently in perihilar cholangiocarcinoma (pCCA, 22.2%). Trop-2 high and medium expression were observed in 69.5% and 20.1% of patients, respectively; its expression was low in intrahepatic cholangiocarcinoma (iCCA, 27.3%). CLDN18 expression showed no adverse clinicopathologic features. High expression of Trop-2 was linked to higher T category and more frequent lymphovascular and perineural invasion. Neither biomarker was significantly associated with overall survival (OS) or disease-free survival (DFS).

Conclusions: CLDN18 was highly expressed in specific BTC subtypes, particularly perihilar cholangiocarcinoma (pCCA) and gallbladder cancer, while Trop-2 was broadly expressed. These findings supported the potential of CLDN18.2- and Trop-2-directed therapies in BTC.

Background: MDM2 regulates the P53 pathway and is a promising therapeutic target, particularly in pediatric cancers with wild-type (WT) TP53. Idasanutlin is an investigational MDM2 inhibitor that is highly selective and orally bioavailable. The combination of MDM2 inhibition with cytotoxic chemotherapy or Bcl-2 inhibition has been shown to improve activity in preclinical models.

Objective: iMATRIX idasa was designed to assess the safety, pharmacokinetics, and antitumor activity of idasanutlin in children and young adults with relapsed/refractory solid tumors.

Patients and methods: This multicenter phase I/II study enrolled patients aged < 30 years with extracranial solid tumors. Patients received idasanutlin on days 1-5 of a 28-day cycle as a single agent or in combination with venetoclax or chemotherapy. The single-agent dose escalation utilized a modified continual reassessment method. The primary endpoints included the safety and determination of the maximum tolerated dose, characterization of the pharmacokinetics, and preliminary efficacy.

Results: Of 38 patients (median age 9 years [range: 2-23]), 26 with solid tumors received idasanutlin alone, and 12 with neuroblastoma received it in combination: six with venetoclax and six with chemotherapy (cyclophosphamide/topotecan). In total, 5 of 26 patients (19.2%) treated with single-agent idasanutlin experienced dose-limiting toxicities (including thrombocytopenia, neutropenia, and febrile neutropenia), which established a pediatric recommended phase II dose for idasanutlin of 4.5 mg/kg/day on days 1-5 of each 28-day cycle. The most frequently reported treatment-related adverse events were thrombocytopenia and neutropenia. Tolerable exposures were similar to what has been observed in adults. The objective response rate for patients with WT TP53 neuroblastoma who were treated with idasanutlin in combination with venetoclax or chemotherapy (primary efficacy endpoint) was 11.1% (N = 9; 95% confidence intervals, CI 0.28, 48.25) with one patient having a complete response. No other patients in the overall study population had an objective response.

Conclusions: The safety profile and tolerable exposure of idasanutlin in pediatrics was similar to that reported in adults. Limited clinical activity was observed in patients with solid tumors. On the basis of the negative benefit-risk assessment, the study was terminated, and the overall pediatric development program for idasanutlin was discontinued.

Clinical trial registration: ClinicalTrials.gov NCT04029688, registered 19 July 2019.

Background: KRAS^G12D is one of the most prevalent driver mutations in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal adenocarcinoma (CRC). Although this genetic alteration is associated with poor prognosis and resistance to chemotherapy, additional genomic features may contribute to the behavior of KRAS-mutant PDACs and CRCs.

Objective: Here, we aimed at defining the landscape of these additional genomic features of KRAS^G12D-mutant PDAC and CRC, and their impact on clinical outcomes.

Patients and methods: This retrospective analysis utilized circulating tumor DNA data from two cohorts with advanced CRC and PDAC: a national cohort from Guardant (n = 27,497) and a Mayo Clinic cohort (n = 1434). Patients were categorized into three groups: KRAS^G12D alone, KRAS^G12D with putative resistance alterations, and KRAS not detected (ND). Genomic co-occurrences were summarized. Overall survival (OS) was compared among groups using Kaplan-Meier and multivariable survival analysis.

Results: Among patients with KRAS^G12D mutation, additional oncogenic alterations were detected in 34.5% of CRC and 11.5% of PDAC in the national cohort; 38.9% of CRC, and 17.4% of PDAC in the Mayo cohort. Common additional oncogenic alterations included EGFR amplifications, additional KRAS point mutations, and alterations in NRAS, BRAF, and PIK3CA. Patients with KRAS^G12D and these alterations had significantly shorter median OS compared with those with KRAS^G12D alone and KRAS ND for CRC (p < 0.0001) and PDAC (p < 0.0001). Presence of KRAS^G12D and additional oncogenic alterations was the only variable significantly associated with OS outcomes in both CRC and PDAC.

Conclusions: We described the genomic landscape of KRAS^G12D-mutant CRC and PDAC, demonstrating that cases often have additional oncogenic alterations linked to resistance to KRAS inhibition. These alterations are also associated with a worse prognosis. Recognizing these alterations may inform new therapeutic strategies. Further studies are warranted to validate these findings in ongoing clinical trials.

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: 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.

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.