This is a summary of a research article reporting the findings of the HER2CLIMB-05 trial (NCT05132582), a randomized, double-blind, placebo-controlled, international, phase III trial. The HER2CLIMB-05 trial was conducted to compare the efficacy and safety of adding tucatinib versus placebo to first-line maintenance therapy (trastuzumab and pertuzumab) following induction chemotherapy, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. The key finding of the HER2CLIMB-05 trial was that progression-free survival was significantly improved in the tucatinib arm over the control arm (24.9 vs 16.3 months). The safety profile of tucatinib plus maintenance therapy was consistent with the known toxicities of each individual drug. The HER2CLIMB-05 regimen, with its high efficacy and manageable toxicity, represents a valuable option for first-line maintenance therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

MET exon 14 (METex14) skipping is observed in approximately 3-4% of patients with non-small-cell lung cancer (NSCLC). These patients are typically older and may or may not have a history of tobacco use. Several small molecule MET tyrosine kinase inhibitors (TKIs) have been developed, showing clinical efficacy in trials targeting the MET pathway in these patients. Among these MET TKIs, tepotinib and capmatinib are globally approved and have demonstrated robust and durable efficacy in patients with METex14 skipping NSCLC in the VISION and GEOMETRY mono-1 trials. While MET TKIs have provided an important therapeutic option for patients with METex14 skipping NSCLC, they are associated with some challenging treatment-related adverse events (TRAEs). Across studies investigating MET TKIs, peripheral edema (49-68%) was reported as the most frequently observed TRAE and is widely recognized as a class effect of MET TKIs in patients with METex14 skipping NSCLC. Nausea (23-44%) and blood creatinine increase (22-34%) were other commonly reported TRAEs observed with treatments in this class. Effective treatment with MET TKIs relies on early recognition of AEs, regular monitoring, patient and caregiver education, and tailored supportive care interventions to ensure treatment continuity and optimal outcomes. Dose reductions have proven effective in mitigating AEs while preserving efficacy, by allowing patients to continue to receive efficacious targeted therapy. In this podcast article, the authors will discuss safety considerations with MET TKI treatment for patients with METex14 skipping NSCLC. They will also share their perspectives on the current landscape of MET TKIs in METex14 skipping NSCLC, commonly reported TRAEs in clinical practice, management strategies for these TRAEs, and safety considerations when switching one MET TKI to another. In addition, authors will discuss two patient cases to illustrate effective management of TRAEs associated with MET TKIs in patients with METex14 skipping NSCLC.

Oral osimertinib (TAGRISSO[®]) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It is approved in several countries (including China, EU, Japan and the USA) for use in combination with platinum-pemetrexed chemotherapy as first-line treatment for adult patients with advanced non-small cell lung cancer (NSCLC) (EU) or locally advanced or metastatic NSCLC (USA) whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations. In the pivotal phase III FLAURA2 trial in this patient population, osimertinib plus platinum-pemetrexed significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared with osimertinib monotherapy. Osimertinib plus platinum-pemetrexed had a manageable tolerability profile, with safety consistent with that of the individual agents, and no new safety signals were identified. In conclusion, osimertinib plus platinum-pemetrexed is a valuable addition to the first-line treatment options for EGFR-mutated, locally advanced or metastatic NSCLC.

Within 20 years of diagnosis, up to 27% of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer will experience recurrence, despite standard-of-care treatments. Of these recurrences, approximately half will occur within 5 years of diagnosis, regardless of disease stage or nodal status. The majority of recurrences are metastatic, for which there is currently no cure. Patients may not fully discern the incurable and potentially distant nature of disease recurrences, or they may be unaware the risk of recurrence exists. Gaps remain in awareness, understanding, and communication around recurrence risk between healthcare professionals and patients. Thus, in addition to understanding the clinical trial and real-world data on recurrences, it is also important to amplify the patient perspective on the impact of recurrence risk to facilitate effective shared decision making. This podcast will bring together physician and patient advocate experts to discuss the risk of recurrence for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer including early and late risk of recurrence, discuss how risk is assessed, and examine the evolving treatment landscape for reducing risk. Supplementary file1 (MP4 310486 KB).

Chimeric antigen receptor (CAR) T-cell therapies represent a distinct therapeutic modality whose clinical activity is governed by in vivo cellular kinetics. Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed, 4-1BB CAR T-cell product in which in vivo expansion plays an important role in clinical pharmacology assessments. Across B-cell malignancies, characterization of liso-cel cellular kinetics demonstrates substantial interindividual variability in expansion, with no single evaluated clinical covariate exerting a clinically meaningful effect. Higher in vivo expansion has been associated with both efficacy and safety outcomes; however, interpretation of these relationships requires careful consideration of end point selection, baseline confounding, and outcome-specific biological context. Particularly, expansion-efficacy relationships are associative rather than causal and are influenced by baseline clinical characteristics and how efficacy end points are defined and assessed. Expansion-safety relationships are end point-dependent, reflecting dynamic immune interactions in the setting of cytokine release syndrome and predominantly downstream toxicity for neurological events. Other clinical pharmacology considerations, including retreatment, persistence, B-cell aplasia, and immunogenicity, further inform the interpretation of liso‑cel expansion within a broader clinical and biological framework. Collectively, these findings indicate that assessing in vivo liso-cel expansion provides important contextual clinical pharmacology information but does not establish it as an independent or deterministic driver of clinical outcomes.

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% of tumor cells), human epidermal growth factor receptor 2-negative advanced disease. Emerging strategies, including antibody-drug conjugates, bispecific antibodies, and chimeric antigen-T-cell therapies, are under active investigation. Claudin-18.2 has established itself as a validated therapeutic target in gastric and gastroesophageal junction adenocarcinoma. Its integration into clinical practice reflects a shift toward biomarker-driven, multi-target treatment algorithms, although challenges remain regarding assay standardization, resistance mechanisms and optimal therapeutic sequencing alongside human epidermal growth factor receptor 2, microsatellite instability/deficient mismatch repair, and programmed death-ligand 1.

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.

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.

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.