The therapeutic paradigm for advanced hepatocellular carcinoma has shifted with the global adoption of immune checkpoint inhibitor-based regimens, leading to the frequent use of multi-tyrosine kinase inhibitors in later treatment lines. This study aimed to evaluate the real-world efficacy and safety of regorafenib as a later-line salvage therapy compared with its conventional second-line application within contemporary clinical practice. This study included 255 patients with advanced hepatocellular carcinoma treated with regorafenib between 2017 and 2026. Clinical outcomes, including objective response rate, disease control rate, overall survival (OS), progression-free survival (PFS), and time to progression, were compared between patients receiving regorafenib as a second-line versus later-line therapy. Of the 255 enrolled patients, 209 received regorafenib as a second-line therapy and 46 as a later-line therapy. The mean maintained dose was significantly lower in the later-line group than in the second-line group. The overall objective response rate and disease control rate were 11.0
Gastric and gastroesophageal junction adenocarcinoma remains associated with a poor prognosis despite recent therapeutic advances. Claudin-18.2, a tight junction protein normally restricted to gastric epithelial cells, has emerged as a clinically validated and therapeutically actionable biomarker due to its preserved expression and aberrant membrane accessibility in malignant tissues. We conducted a narrative review of the literature (PubMed/MEDLINE and ClinicalTrials.gov; January 2000-December 2025) to summarize current knowledge on Claudin-18.2 biology, expression patterns, clinical relevance, and therapeutic targeting in gastric and gastroesophageal junction adenocarcinoma. Claudin-18.2 is frequently retained in gastric and gastroesophageal junction adenocarcinoma and can be reliably assessed using standardized immunohistochemistry. The phase III SPOTLIGHT and GLOW trials demonstrated that zolbetuximab significantly improves progression-free survival and overall survival when combined with first-line chemotherapy in Claudin-18.2-positive (moderate [2+] to strong [3+] membranous staining in ≥ 75
Gastrointestinal stromal tumors are the most common sarcomas of the gastrointestinal tract. They are characterized by a distinct molecular profile, most frequently involving activating mutations in the KIT or PDGFRA genes, the identification of which has enabled the development of effective targeted therapies and has significantly improved patient outcomes. Despite significant therapeutic advances, treatment with tyrosine kinase inhibitors remains associated with the risk of primary or secondary resistance in a subset of patients. This phenomenon has highlighted the considerable biological heterogeneity of gastrointestinal stromal tumor, encompassing not only canonical mutational variants but also rare molecular alterations with distinct pathogenic mechanisms and clinical implications. Growing evidence suggests that detailed molecular characterization of gastrointestinal stromal tumors is of critical clinical importance, enabling improved risk stratification, optimization of treatment selection, and identification of patients requiring alternative therapeutic strategies. Therefore, comprehensive molecular diagnostics should be an integral part of the diagnostic and therapeutic approach to this heterogeneous group of tumors. The aim of this study is to provide an overview of current knowledge on rare molecular variants of gastrointestinal stromal tumors, as well as the available data on their clinical course and sensitivity to tyrosine kinase inhibitors and other therapeutic strategies.
Prostate cancer represents the third leading cause of cancer-related mortality in the male population. Androgen deprivation therapy efficacy has been significantly enhanced by the addition of docetaxel chemotherapy and androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, apalutamide, and darolutamide. These agents have demonstrated improvements in both overall survival (OS) and progression-free survival (PFS). Nevertheless, a subset of patients eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). The prostate-specific antigen (PSA) nadir, defined as the lowest PSA level achieved during therapy, has emerged as an early surrogate marker of treatment response and favorable prognosis. We conducted a meta-analysis to elucidate the prognostic value of the depth of PSA response in patients with metastatic metastatic hormone-sensitive prostate cancer (mHSPC) treated with ARPI or docetaxel. This is a reconstructed individual patient data (IPD) meta-analysis, in which prospective and retrospective clinical trials concerning patients with mHSPC who received first-line therapy with an ARPI or docetaxel were included. Prospective or retrospective studies on mHSPC patients with available data on the lowest value of PSA reached were included. IPD from the Kaplan–Meier curves of enrolled studies were obtained with the software IPDfromKM. Primary endpoints of the analysis were overall survival (OS) and progression-free survival (PFS) in patients who reached a PSA nadir ≤ 0.2 versus PSA nadir > 0.2. A total of 8 reports from 8 studies were included, collecting data from 1638 patients for the OS analysis and 1104 for the PFS analysis. In terms of median PFS (mPFS), the PSA nadir ≤ 0.2 arm had an advantage: mPFS not reached (NR) versus 12.1 months HR 0.19 (95
To date, there have been no head-to-head randomized controlled trial data comparing cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in patients with HR+/HER2− metastatic breast cancer (mBC), and most prior real-world comparative effectiveness studies have been limited by short follow-up times and small patient sample sizes. In this vodcast, we provide an overview of two recent publications reporting overall survival (OS) and real-world progression-free survival (rwPFS) results from P-VERIFY, a retrospective comparative effectiveness study of CDK4/6 inhibitors plus an aromatase inhibitor (AI) among patients with HR+/HER2− mBC treated in routine clinical practice in the USA. P-VERIFY used the Flatiron Health Analytic Database to identify 9146 patients who initiated first-line (1L) treatment with palbociclib (n = 6831), ribociclib (n = 1279), or abemaciclib (n = 1036), plus an AI, between February 2015 and November 2023. In primary analyses, there were no significant differences in OS and rwPFS between treatment groups after stabilized inverse probability treatment weighting, with hazard ratios ranging from 0.95 to 0.98 across pairwise group comparisons (all P > 0.05). Findings remained generally consistent across sensitivity and subgroup analyses and in a subanalysis of patients who started treatment in 2017 or later, when all three CDK4/6 inhibitors were commercially available. Taken together, results from P-VERIFY, the largest real-world study to date evaluating CDK4/6 inhibitor comparative effectiveness, suggest that there are no significant differences in OS and rwPFS between 1L palbociclib, ribociclib, and abemaciclib, plus an AI, in patients with HR+/HER2− mBC in US routine clinical practice.
Intravenous (IV) amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for multiple indications alone or in combination for patients with EGFR-mutated advanced or metastatic nonsmall cell lung cancer (NSCLC). In the PALOMA-3 study, subcutaneous (SC) amivantamab was investigated to improve tolerability, reduce administration time, maintain efficacy, and improve patient experience. This vodcast reviews the rationale and data supporting SC amivantamab on the basis of the PALOMA-3 study and provides expert-led recommendations for SC amivantamab treatment. The PALOMA-3 study investigated the noninferiority of pharmacokinetics, with other endpoints including efficacy and safety of SC versus IV amivantamab, combined with lazertinib in participants with EGFR-mutated, advanced NSCLC after disease progression on osimertinib and platinum-based chemotherapy. Geometric mean ratios of Ctrough for SC to IV amivantamab were 1.15 at Cycle 2 Day 1 (C2D1) and 1.42 at C4D1; C2AUCD1-D15 was 1.035. Objective response rate (ORR) was 30
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have significantly changed the treatment approach for hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HER2−) breast cancer in both metastatic and high-risk early-stage settings. In combination with endocrine therapy, these agents consistently improve progression-free survival, and several phase III trials have demonstrated overall survival benefit in defined populations. Their clinical activity is supported by a well-established biologic rationale targeting dysregulated cell cycle progression, a key feature of HR+ breast cancer, which drives tumor proliferation. Despite these advances, resistance remains a clinical limitation in advanced disease. Multiple mechanisms have been identified, including loss of RB1 function; amplification of CDK6, activation of cyclin E CDK2 signaling; upregulation of bypass pathways such as PI3K, AKT, mTOR, and FGFR; and acquired alterations in estrogen receptor signaling, including ESR1 mutations. Circulating tumor DNA assays are increasingly used in clinical practice and clinical trials to detect emerging genomic alterations that may allow earlier modification of therapy based on molecular progression. The post-CDK4/6-inhibitor treatment landscape has expanded substantially and now includes treatment options such as switching CDK4/6 inhibitors, targeting the PI3K–AKT pathway in patients selected for mutation, use of oral selective estrogen receptor degraders, and incorporation of antibody–drug conjugates. Ongoing studies evaluating CDK2 inhibitors, CDK4-selective agents, immunotherapy combinations, and circulating tumor DNA (ctDNA)-guided strategies aim to further refine treatment sequencing and improve long-term outcomes in HR+/HER2− breast cancer.
FGF/FGFR alterations are recurrent but heterogeneous in head and neck cancer, and which types predict benefit from selective fibroblast growth factor receptor (FGFR) inhibition is unknown. We examined whether response to gunagratinib, a pan-FGFR1–4 inhibitor, differs by FGF/FGFR alteration type in recurrent or metastatic head and neck cancer. Patients with recurrent or metastatic head and neck cancer and fibroblast growth factor(FGF)/FGFR alterations treated with gunagratinib in two prospective trials were combined (phase I ICP-CL-00301, n = 10; phase IIa ICP-CL-00304 at the recommended phase II dose [RP2D] of 20 mg once daily, n = 27). Confirmed objective response rate (Response Evaluation Criteria in Solid Tumours [RECIST] Version 1.1, investigator assessed) was the primary endpoint. Exploratory analyses examined efficacy by alteration type, with an RP2D sensitivity analysis and post-hoc CCND1 outcomes. Among 37 patients (23 head and neck squamous cell carcinoma, 9 nasopharyngeal carcinoma, 5 other; 78.4
Hepatocellular carcinoma is one of the most common cancers worldwide and the third leading cause of cancer-related mortality. The therapeutic landscape of hepatocellular carcinoma, especially systemic therapies, is constantly changing and characterized by a multimodal approach. The aim of this study was to investigate whether and how treatment sequencing according to tumor stage and liver function has changed over time and if the introduction of new therapeutic options has led to improved survival rates. Therapy concepts were retrospectively recorded and evaluated in a cohort of 1288 patients with hepatocellular carcinoma with a first diagnosis between January 2013 and December 2022 who were divided into two cohorts with a cut-off for dividing in 2020 owing to the approval of atezolizumab and bevacizumab for the treatment of hepatocellular carcinoma by the European Medicines Agency (Cohort A initial diagnosis 2013–19, Cohort B initial diagnosis 2020–22). All patients were treated at Hannover Medical School, Germany. Baseline characteristics differed significantly between cohorts, with Cohort B presenting at earlier tumor stages and with better preserved liver function. Across all treatment modalities, liver function emerged as the primary determinant of prognosis, independent of tumor stage and performance status. Over time, a treatment shift from transarterial chemoembolization towards systemic therapies was observed. Median overall survival from initial diagnosis did not differ between cohorts. In unadjusted analyses, patients treated with immune checkpoint inhibitor-based regimens demonstrated longer median overall survival compared with those receiving tyrosine kinase inhibitors. However, after multivariable adjustment for baseline imbalances, no independent survival difference between treatment groups remained. This study provides a detailed longitudinal assessment of evolving treatment patterns and outcomes, highlighting a clear shift in therapeutic strategies over time with the increasing adoption of systemic therapies. Despite evolving treatment strategies and increased use of systemic therapies, liver function remained the dominant prognostic factor across treatment settings. Observed survival differences between treatment modalities were strongly influenced by baseline patient characteristics and treatment selection.
For the past decades, chemotherapy constituted the therapeutic foundation in advanced or metastatic pancreatic cancer. Despite significant advances in the molecular understanding, translation into tangible patient benefit has remained modest. Until recently, mutant KRAS, the dominant oncogenic driver, was considered undruggable, and only a small subgroup of patients potentially benefited from targeted therapies. With the emergence of KRAS inhibitors, most patients with pancreatic cancer in theory qualify for targeted therapeutics. Final results from the RASolute 302 trial showed clinically meaningful activity of RAS inhibition in patients with metastatic pancreatic cancer and paved the way for approval. Ongoing preclinical and coclinical studies have documented both intrinsic and acquired mechanisms of resistance to KRAS inhibition. Given the cellular plasticity seen in pancreatic cancer, the identification and anticipation of resistance mechanisms will be critical to exploit emerging therapeutic vulnerabilities through novel combination strategies. In view of the increasing number of trials and the growing body of evidence for targeted therapies, pancreatic cancer is entering a transitional phase in which precision oncology strategies must be redefined beyond rare molecular subgroups. In this review, we will briefly revisit targeted therapeutic approaches in pancreatic cancer to then discuss the clinical implications of genomic and transcriptomic heterogeneity in KRAS-mutant and KRAS wild-type disease. We will outline how our expanding biological insights into pancreatic cancer could inform combination and sequential therapeutic approaches.
Molecular tumor boards (MTBs) support precision oncology by translating genomic profiling into evidence-based treatment recommendations, for example according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT). Their clinical utility in real-world care depends on effective implementation within healthcare systems. To evaluate the implementation rate of MTB recommendations, associated determinants, and clinical outcomes in a real-world single-center cohort. At a single-center MTB, 582 consecutive cases (2020–2023) were retrospectively analyzed, with last survival follow-up in August 2025. Patient demographics, tumor characteristics, genomic alterations, ESCAT and ZPM (Zentrum für Personalisierte Medizin) evidence levels, targeted therapy recommendation and implementation rates, survival outcomes, and barriers to implementation were evaluated using descriptive and inferential statistics, as appropriate. Of 582 patients (median age 61 years, 48.5
Melanoma has an excellent prognosis when detected at a localized stage, but when patients present with regional or distant metastases, 5-year survival decreases to approximately 76
Abiraterone (ABI) and enzalutamide (ENZA) are standard treatments for metastatic castration-resistant prostate cancer (mCRPC). However, their safety and efficacy have not been directly compared in prospective clinical trials. To directly compare their safety and efficacy in prospective clinical trials. A systematic search was performed in PubMed, Embase, and Cochrane Library databases (CRD42024608496) on 24 June 2025. Eligibility criteria included studies on patients with mCRPC treated with ABI or ENZA reporting outcomes such as overall survival (OS), prostate-specific antigen (PSA) response (PSA50/90), progression-free survival (rPFS/bPFS), and rates of grade ≥ 3 adverse events, dose reduction, treatment discontinuation, and major cardiovascular events (MACE). Both first- and second-line mCRPC treatment settings were considered. The inverse variance method was used to calculate pooled hazard ratios (HRs), using the natural logarithm of the HR and its standard error (SE) from the available data. A total of 47 real-world observation studies and data from 71,984 patients were included, with no randomized controlled trials available for direct comparison. ENZA proved more effective in terms of PSA50 (odds ratio (OR): 1.82; 95
Chimeric antigen receptor (CAR)-T cell therapy has demonstrated substantial efficacy in hematologic malignancies; however, its application in pediatric and young adult primary central nervous system (CNS) tumors, particularly pediatric diffuse midline glioma (DMG), remains investigational. Several early phase trials have recently reported clinical experiences with CNS-directed CAR-T cell therapies, necessitating a systematic distillation to better understand the state of the field. The aim of the study was to systematically review early phase clinical evidence evaluating the safety, feasibility, and preliminary efficacy of CAR-T cell therapy in pediatric and young adult patients with primary CNS tumors. A systematic review was conducted on early phase clinical studies assessing CAR-T cell therapies in pediatric and young adult patients diagnosed with primary brain tumors. Data collected included information on antigen targets, route of administration, dosing strategies, patient characteristics, prior therapies, toxicity profiles, anti-inflammatory management, radiographic and clinical outcomes, biologic correlates, and survival. The search identified eight early phase trials involving 74 pediatric and young adult patients. Of the cohort, 63 received CAR-T cell infusion, targeting B7-H3, GD2, HER2, EGFR806, and PSMA-GD2 via intraventricular, intravenous, or combined routes. All patients had heavily pretreated, recurrent, or refractory disease, with all DMG cohorts receiving prior radiation. CAR-T cell therapy was feasible, with no treatment-related mortality. Immune toxicities, including cytokine release syndrome and CNS neurotoxicity, were common but reversible with corticosteroids and cytokine therapies. Among response-evaluable patients, 65
To date, there are limited clinical trials comparing the clinical efficacy between second-generation and third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI)s. The objective of this study was to compare the survival outcomes between afatinib and osimertinib as first-line treatments in patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC). Between January 2018 and December 2020, we retrospectively enrolled patients with advanced NSCLC harboring an exon 19 deletion or L858R mutation who received afatinib or osimertinib as first-line treatment to analyze the progression-free survival (PFS) and overall survival (OS). A total of 128 patients were included in this study, with 81 in the afatinib group and 47 in the osimertinib group. The median follow-up time was 39.9 months for the afatinib group and 37.0 months for the osimertinib group. The median PFS was 13.5 months in the afatinib group and 18.2 months in the osimertinib group (p = 0.240). The median OS was 40.5 months in the afatinib group and 37.0 months in the osimertinib group (p = 0.980). A total of 63
Real-world data on adjuvant pembrolizumab after surgery for renal cell carcinoma (RCC) are limited. To clarify the real-world outcomes of adjuvant pembrolizumab for patients with RCC with a high risk of recurrence. We retrospectively evaluated the clinicopathological data of 53 patients who received pembrolizumab as an adjuvant therapy after curative surgery for RCC on the basis of the criteria of the KEYNOTE-564 trial. The efficacy and safety profiles were assessed. The potential of PD-L1 expression as a biomarker of recurrence was evaluated in 35 RCC samples using the combined positive score (CPS). The median follow-up period was 18.9 months. On the basis of the KEYNOTE-564 criteria, 45 patients (85
Frontline systemic therapy for metastatic clear cell renal cell carcinoma (RCC) has evolved to include doublet immunotherapy (IO/IO) and immunotherapy-tyrosine kinase inhibitor combinations (IO/TKI), with selection typically guided by histology and risk stratification. However, optimal regimen selection remains undefined owing to limited head-to-head data. Subanalyses of landmark clinical trials and emerging real-world multicenter study data suggest differential treatment benefit derived by metastatic site, particularly for bone metastases. Evidence suggests that bone metastases promote an immunosuppressive tumor microenvironment and may preferentially upregulate genes encoding angiogenic factors, compared with other sites. Such biology-driven patterns provide a rationale for the hypothesis that IO/TKI may confer greater activity in bone-predominant disease. Liver metastases may also exhibit similar site-specific patterns due to harboring an immunosuppressive and vascular environment, but RCC-specific data remain scarce. This overview summarizes the mechanistic rationale, clinical evidence, and practical implications of tailoring treatment by disease site, highlighting critical gaps as well as future research priorities.
Immune checkpoint inhibitor (ICI)-based regimens are the standard first-line therapy for advanced renal cell carcinoma (RCC). However, their comparative effectiveness and safety in routine clinical practice remain incompletely characterised. The aim of this study was to systematically synthesise comparative real-world evidence on the efficacy and safety of ICI-based regimens in patients with advanced RCC. A systematic search of MEDLINE, Embase, and Scopus was conducted from database inception to 21 January 2026, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Observational cohort studies evaluating ICI-based regimens in advanced RCC with an active comparator were included. Primary efficacy outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety outcomes included treatment-related adverse events. Study quality was assessed using the Newcastle–Ottawa Scale, with efficacy and safety evaluated separately. Owing to substantial clinical and methodological heterogeneity, findings were synthesised narratively. Overall, 58 retrospective cohort studies comprising 35,215 patients were included. Most studies evaluated first-line therapy and involved populations with mixed histology and heterogeneous prognostic risk profiles. Overall, ICI-tyrosine kinase inhibitor (TKI) combinations were generally associated with more favourable survival outcomes compared with dual ICI therapy or TKI monotherapy, with the most consistent benefit observed for PFS. Evidence comparing dual ICI therapy with TKI monotherapy was mixed, with most studies reporting no statistically significant differences in survival outcomes. Comparative safety data were limited, with the majority of studies relying on unadjusted descriptive analyses, limiting robust comparative interpretation of safety outcomes. Real-world evidence suggests that ICI–TKI combinations are associated with more favourable survival outcomes compared with other treatment options in advanced RCC, while the comparative effectiveness of dual ICI therapy versus TKI monotherapy remains inconclusive. Substantial heterogeneity and methodological limitations, particularly in safety reporting, limit definitive interpretation. High-quality real-world studies incorporating robust confounding adjustment and clinically relevant subgroup analyses are needed to better inform treatment selection in routine practice. International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD420251149614.
In the first episode of our podcast series, we introduce the emerging landscape of HER2-mutant non-small cell lung cancer (NSCLC), highlighting its place within the broader context of lung cancer. We explain what makes HER2-mutant NSCLC unique, from its epidemiology and biology to the molecular mechanisms driving cancer growth. We discuss the evolution of precision medicine in NSCLC, the role of HER2 as a therapeutic target, and how advances in molecular profiling have enabled the development of targeted therapies. The episode also covers the latest treatment strategies, including antibody–drug conjugates and tyrosine kinase inhibitors, and reviews the challenges and opportunities that define this aggressive cancer subtype. This podcast aims to enhance understanding of HER2-mutant NSCLC and the evolving therapeutic landscape that is reshaping management strategies for this aggressive disease.
