Targeted Oncology最新文献

Breast cancer remains a leading cause of cancer-related mortality despite advances in targeted therapies and immune checkpoint inhibitors (ICIs). While ICIs have reshaped therapeutic paradigms in multiple solid tumors, their clinical efficacy in breast cancer is predominantly restricted to triple-negative breast cancer (TNBC), underscoring the necessity for innovative immunotherapeutic modalities with broader applicability. Bispecific antibodies (BsAbs) are engineered molecules capable of simultaneously engaging tumor-associated antigens (TAAs) such as EGFR, EpCAM, Trop-2, CEACAM5, MUC1, and PSMA, in addition to B7-H4, HER2, and PD-L1, alongside immune effector cells, primarily CD3+ T lymphocytes. This dual targeting promotes the formation of a cytolytic immunological synapse, leading to T-cell activation, proliferation, and targeted tumor cell lysis via granzyme/perforin pathways. Advances in BsAb design-including optimization of affinity constants, valency, Fc engineering to modulate effector functions, and molecular formats (e.g., BiTEs, DARTs, tandem scFvs)-have improved tumor penetration, pharmacokinetics, and reduced off-target toxicity. Preclinical and early-phase clinical data demonstrate robust antitumor activity of BsAbs, both as monotherapy and in synergistic combinations with chemotherapy, targeted agents, or ICIs, potentially overcoming tumor microenvironment-mediated immunosuppression and immune escape mechanisms. Major challenges include heterogeneity and temporal variability of TAA expression, cytokine release syndrome (CRS) mitigation strategies, pharmacodynamic optimization, and delivery methods to maximize tumor bioavailability while limiting systemic toxicity. This review details the molecular mechanisms, preclinical evidence, clinical trial outcomes, and translational challenges for BsAbs in breast cancer, highlighting their transformative potential in expanding immunotherapeutic efficacy beyond current limitations.

The podcast discusses the available treatment options for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) and focuses on the efficacy and safety of first-line treatments and sequencing strategies. Patients with ALK-positive NSCLC often need multiple lines of therapy owing to the development of resistance, disease progression, brain metastases, or adverse events. Several options are available for the treatment of ALK-positive NSCLC; therefore, it is important to make an informed decision on which treatment to use in the first line. The podcast also discusses the challenges in treatment sequencing due to high attrition rates from first-line to second-line therapy and the decline in treatment efficacy with each additional line. Real-world data indicate that many patients do not receive second-line therapy after discontinuing first-line treatment. The discussion emphasizes the importance of consideration of drug efficacy, safety outcomes, potential treatment resistance, and development of brain metastases when determining treatment strategies. Ultimately, it is essential to select the best treatment first and proactively manage any potential adverse events to ensure that patients can derive clinical benefit and safely remain on therapy.

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: Given that immune checkpoint inhibitor-based regimens frequently yield delayed separation and late plateaus, conventional hazard ratio analyses that assume proportional hazards may misstate true benefit.

Objective: We aimed to test the validity of the proportional hazards assumption in first-line metastatic clear cell renal cell carcinoma trials and to compare the immune checkpoint inhibitor-based regimens using restricted mean survival time.

Methods: We performed a systematic review and network meta-analysis of phase III randomized controlled trials of first-line treatment for metastatic clear cell renal cell carcinoma, including immune checkpoint inhibitor-tyrosine kinase inhibitor combinations or dual-immune checkpoint inhibitor regimens. Individual patient data were reconstructed from the Kaplan-Meier curves of overall survival and progression-free survival. The restricted mean survival time differences were estimated.

Results: Five trials (4206 patients; six treatment arms) were examined. Proportional hazards assumption was violated in 60% of both overall survival and progression-free survival comparisons. In the restricted mean survival time-based network meta-analysis of overall survival, immune checkpoint inhibitor-tyrosine kinase inhibitor combinations, especially Nivolumab + Cabozantinib, dominated at 12-48 months, whereas Ipilimumab + Nivolumab ranked highest beyond 48 months. In the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable-risk subgroup, Avelumab + Axitinib showed a favorable long-term profile despite the lack of statistical significance. In IMDC intermediate/poor-risk, patterns mirrored the overall population. For progression-free survival, Pembrolizumab + Lenvatinib ranked best across IMDC subgroups. Limitations included the reliance on reconstructed data and heterogeneity across trials.

Conclusions: Given the frequent proportional hazards violations, hazard ratio-only syntheses are insufficient for modern immune checkpoint inhibitor-based regimens. In the restricted mean survival time-based network meta-analysis, Pembrolizumab + Lenvatinib delivered rapid disease control, and Ipilimumab + Nivolumab showed the greatest late survival advantage in IMDC intermediate/poor-risk.

Prospero registration number: CRD420251143602.

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: Hormone receptor-positive/human epidermal growth factor receptor 2-positive (HR+/HER2+) breast cancer accounts for approximately 10% of breast cancer cases and is associated with therapeutic resistance and variable clinical outcomes. Preclinical studies suggest that CDK4/6 inhibition may enhance the activity of combined endocrine and HER2-targeted therapy.

Objective: To summarize and synthesize available clinical trial evidence evaluating CDK4/6 inhibitors in metastatic HR+/HER2+ breast cancer.

Patients and methods: We conducted a systematic review and descriptive meta-analysis of four clinical trials evaluating CDK4/6 inhibitors in combination with endocrine and anti-HER2 therapy in metastatic HR+/HER2+ breast cancer. A random-effects model was used to summarize pooled efficacy outcomes.

Results: The pooled objective response rate was 33%. Complete response occurred in 2% of patients, partial response in 35%, and stable disease in 40%, and the clinical benefit rate was 69%. Substantial heterogeneity was observed across studies.

Conclusions: Across available clinical trials, CDK4/6 inhibitor-based combination therapy was associated with disease control in a subset of patients with metastatic HR+/HER2+ breast cancer. Given the heterogeneity of study designs and limited comparative data, these findings should be interpreted cautiously and support the need for further randomized trials to better define optimal treatment strategies and patient selection.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been standard of care as monotherapy for EGFR-mutated advanced non-small cell lung cancer since reporting of the FLAURA phase III clinical trial, which demonstrated superiority over first-generation EGFR tyrosine kinase inhibitors. Efforts to improve efficacy have led to combination therapies with chemotherapy or co-inhibition of EGFR and MET, which have become additional standards. Choosing between these strategies requires careful understanding of disease biology and disease burden, and joint decision making with patients. Despite increasing understanding of acquired resistance mechanisms in later-line therapies, advances in the first-line options have made second-line treatment decision making increasingly nuanced. Physicians require an in-depth understanding of the genomics of the disease, and ideally an ability to reassess the tumour genomic/expression profile to guide next-line therapy at each timepoint of progression. Targeting on-target resistance (e.g. C797X mutations) with fourth-generation EGFR tyrosine kinase inhibitors has been disappointing, and in addition to biological challenges, there are regulatory challenges with approaches combining tyrosine kinase inhibitors targeting EGFR and off-target oncogenic resistance kinases. There are multiple broader approaches to improve second^-line outcomes in development, such as antibody drug conjugates, vascular endothelial growth factor (VEGF) inhibition and immunotherapeutic approaches, which further complicate treatment selection in the second- and later-line settings. Optimal therapy selection and treatment sequencing provides a great challenge moving into the future. Here, we provide an overview of current and possible future pharmacotherapeutic strategies in the first- and later-line settings for EGFR-mutated non-small cell lung cancer in the context of new first-line strategies and seek to explore the nuances that may guide treatment selection based on current understanding of this disease.