Oncology and Therapy最新文献

Introduction: FMS-like tyrosine kinase 3 (FLT3) mutations show variable detectability in relapse/refractory acute myeloid leukemia (AML) with unclear clonal evolution dynamics.

Methods: This prospective noninterventional study examined clonal evolution and outcomes from AML diagnosis to relapse/refractory disease occurrences.

Results: Of 650 patients included, 172 were FLT3-positive (FLT3^pos) and 472 were FLT3-negative (FLT3^neg; 99.1% testing rate; unknown FLT3 status, six patients). At first occurrence, the FLT3 testing rate decreased (57.0% [166/291]). Among tested patients, 45 had FLT3^pos and 121 had FLT3^neg AML. A gain or loss of mutations was seen in 15.6% (7/45) of patients with FLT3^pos AML and 14.9% (18/121) of patients with FLT3^neg AML. Median (95% confidence interval [CI]) overall survival was 22.8 (19.6, not estimable [NE]) months across patients (FLT3^pos, NE;FLT3^neg, 20.3 [15.2-23.7] months; hazard ratio [HR] [95% CI] 0.6 [0.5-0.8]). Median (95% CI) disease-free survival across patients was NE (26.3-NE) (FLT3^pos, NE;FLT3^neg, NE; HR [95% CI] 0.8 [0.6-1.1]). Median event-free survival (95% CI) was 11.8 (10.0-15.5) months in all patients (FLT3^pos, 17.2 [11.0-NE] months;FLT3^neg, 10.4 [8.4-13.2] months; HR [95% CI] 0.8 [0.6-1.0]).

Conclusions: Dynamic changes in FLT3 mutation status were observed during these patients' disease course. FLT3^pos status at baseline, but not at first occurrence, was associated with improved outcomes; other confounders should be considered. Timelier FLT3 mutation retesting may aid in personalizing treatment. Graphical abstract available for this article.

Introduction: Squamous nonsmall cell lung cancer (sq-NSCLC) is challenging to treat, with shorter survival when compared with other NSCLC subtypes. Tislelizumab has demonstrated efficacy when combined with chemotherapy for sq-NSCLC. We report 4-year follow-up results from the phase 3 randomized RATIONALE-307 trial evaluating tislelizumab plus chemotherapy as first-line treatment for advanced or metastatic sq-NSCLC.

Methods: Patients with treatment-naive advanced or metastatic sq-NSCLC were randomized to receive tislelizumab plus paclitaxel/carboplatin (arm A), tislelizumab plus nab-paclitaxel/carboplatin (arm B), or paclitaxel/carboplatin alone (arm C) until disease progression/intolerable toxicity. Crossover was permitted from arm C to tislelizumab monotherapy. The primary end point was progression-free survival (PFS) per independent review. Key secondary end points included overall survival (OS) and safety.

Results: At median OS follow-up of 44.8 months, tislelizumab plus chemotherapy demonstrated durable survival benefit. Median PFS was 7.7 months (95% confidence interval [CI] 6.7-9.9) in arm A, 9.5 months (95% CI 7.4-10.1) in arm B, and 5.5 months (95% CI 4.2-5.6) in arm C. Median OS was 26.1 months (95% CI 19.0-33.8) in arm A, 23.3 months (95% CI 18.8-26.4) in arm B, and 19.4 months (95% CI 16.0-23.4) in arm C. The 4-year OS rates were 32.2%, 26.0%, and 19.2% for arms A, B, and C, respectively. Crossover occurred in 58.7% of patients from arm C. OS and PFS benefits were observed across most subgroups. Grade ≥ 3 treatment-emergent adverse events occurred in 89.2%, 89.0%, and 84.6% of patients in arms A, B, and C, respectively. No new safety signals emerged.

Conclusions: At 4-year follow-up, patients with advanced sq-NSCLC who received tislelizumab plus chemotherapy experienced long-term OS and PFS benefits versus chemotherapy alone, despite high crossover rates. The combination was well-tolerated with no new safety concerns. This regimen may be a promising first-line treatment option for patients with advanced or metastatic sq-NSCLC.

Trial registration: ClinicalTrials.gov NCT03594747.

Introduction: Bruton tyrosine kinase inhibitor (BTKi) monotherapies have improved patient outcomes in B cell lymphomas; however, evidence on their comparative efficacy remains limited. This meta-analysis compared the efficacy of BTKi monotherapies across treatment naïve (TN) and/or relapsed and refractory (R/R) B cell lymphomas.

Methods: Clinical trials reporting complete response (CR) or overall response rate (ORR) for zanubrutinib, acalabrutinib, or ibrutinib monotherapy in chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or Waldenström macroglobulinemia (WM) were included. Response rates from similar duration of follow-up were pooled across applicable studies. Naïve odds ratios (ORs) comparing CR and ORR of zanubrutinib with acalabrutinib or ibrutinib were calculated within each B cell lymphoma indication and then meta-analyzed across all indications using a random effects model.

Results: The meta-analysis found zanubrutinib to be associated with statistically significant improvements in investigator-assessed CR and ORR vs acalabrutinib and ibrutinib across B cell lymphomas, using data with similar duration of follow-up. The pooled OR estimates [95% CI] for CR were 1.80 [1.03, 3.13] for zanubrutinib vs acalabrutinib and 2.85 [1.16, 7.04] for zanubrutinib vs ibrutinib across all B cell indications. ORs significantly favored zanubrutinib over acalabrutinib and ibrutinib for R/R MCL, and over ibrutinib for R/R MZL. The pooled OR estimates for ORR were 1.59 [1.00, 2.53] for zanubrutinib vs acalabrutinib and 2.25 [1.40, 3.61] for zanubrutinib vs ibrutinib. ORs significantly favored zanubrutinib over acalabrutinib and ibrutinib for TN CLL, and over ibrutinib for R/R MCL and R/R MZL.

Conclusion: Consistent with the results of existing head-to-head trials, zanubrutinib demonstrated either numerically or statistically significant improved CR and ORR compared to acalabrutinib and ibrutinib across B cell lymphomas. Similar trends were observed within each indication. These findings suggest that zanubrutinib is the most effective BTKi treatment option for patients across B cell lymphomas.

Introduction: Patient interview data exploring the experiences of the most relevant symptoms and impacts of upper tract urothelial cancer (UTUC) remain scarce. This study aimed to develop a conceptual disease model (CDM) of UTUC grounded in patients' own experiences of UTUC and to capture disease-specific symptoms and impacts experienced before, during, and after cancer treatment.

Methods: A targeted literature review (TLR) informed the qualitative interview guide development. Qualitative concept elicitation interviews were then performed with patients who had UTUC to understand their experiences of the disease and its treatment, focusing on symptoms and impacts. Interview transcripts were thematically analyzed using ATLAS.ti^©. The findings from both the TLR and qualitative interviews were synthesized to develop a CDM.

Results: We interviewed 15 adults with UTUC (mean age, 56 years), including nine with low-grade and six with high-grade UTUC. Patients reported 22 symptoms: 11 pre-treatment and 21 during treatment and/or post-treatment. The most frequently reported pre-treatment symptoms were blood in urine (60%), fatigue/tiredness (53%), and pain (47%). During or post-treatment, the most frequently reported symptoms were fatigue/tiredness (93%), pain (47%), and weight loss (40%). Patients with low- and high-grade UTUC reported comparable numbers of distinct symptoms, both pre- and post-treatment. UTUC and its treatment impacted patients' emotional well-being (100%), activities of daily life (73%), relationships (73%), social functioning (60%), sleep (60%), and physical functioning (27%), and treatment burden was explicitly mentioned by 13%. The CDM of UTUC was developed, capturing the symptoms and impacts experienced by patients with low- or high-grade UTUC.

Conclusions: This qualitative study identified a broad range of symptoms and impacts of UTUC and its treatment, highlighting the unmet patient needs associated with current UTUC management. Our findings provide a qualitative foundation to inform endpoint and clinical outcome assessment selections in clinical research and to guide patient-centered care strategies for UTUC.

Introduction: Prostate-specific membrane antigen (PSMA) is a key diagnostic/prognostic, therapeutic target in prostate cancer. While PSMA expression is well established in prostate cancer, its expression is also observed in non-prostatic tissues and other tumors. PSMA expression is observed in salivary gland tumors (SGTs); however, its expression pattern is not well established. This study assessed the distribution of PSMA expression in SGT specimens.

Methods: This study retrospectively analyzed archived SGT specimens. Patient records were reviewed and their formalin-embedded tumor blocks were retrieved from the pathology department files. Immunohistochemical staining and examination was performed using an antibody directed against PSMA to assess expression levels in 243 salivary gland specimens containing 126 specimens of malignant and 117 specimens of benign SGTs. PSMA staining was quantified using a modified immunohistochemical scoring method (H score; range 0-300).

Results: PSMA expression was observed in both benign SGTs and malignant SGTs; however, PSMA expression in malignant SGTs was higher than in benign SGTs. PSMA was expressed in 94% (118/126) of malignant SGTs (represented as average histochemical [H_avg] score, [Havg = 95.2]), and 61% (71/117) of benign SGTs (H_avg = 37.3). Amongst malignant SGT specimens, the highest H_avg scores were observed for adenoid cystic carcinoma (H_avg = 133.7) and acinic cell carcinoma (H_avg = 133.6). Based on the modal staining intensity scoring, strong PSMA staining (staining intensity score = 3) was observed at higher rates in malignant (38%, 48/126) versus benign (18%, 21/117) SGTs.

Conclusion: This study demonstrated that PSMA is commonly expressed in malignant SGTs, suggesting that PSMA could be effective for targeted imaging and therapeutics in these tumor types.

Human epidermal growth factor receptor 2 (HER2) overexpression or amplification of the human ERBB2 oncogene occurs in approximately one-fifth of breast cancers and, of these, two-thirds are hormone receptor (HR)-positive (HR+). The introduction of HER2-targeted therapies in recent years has significantly improved survival outcomes in patients with this tumor subtype. However, disease recurrence risk is 10-30% at 5 years with a different pattern between patients with HER2+/HR+ and HER2+/HR-negative (HR-) early breast cancer, with HR+ patients having a lower risk than those with HR- disease in the first 5 years, but a slightly higher risk at 5-10 years post-surgery. This highlights a crucial need to explore the underlying mechanisms for these differences to address specific treatment needs and to optimize systemic adjuvant treatment outcomes. Therefore, this narrative review provides an overview of published data regarding the recognized factors and ongoing challenges associated with the risk of relapse in women with HER2+ early breast cancer and proposes potential adjuvant treatment strategies to minimize risk of recurrence in high-risk patients.

With a rising incidence globally, there is need to address a basic deficiency, namely, the lack of a clear definition of sporadic early-onset invasive solid organ cancers in adults. This manuscript discusses this need to have a unified understanding of what constitutes sporadic early-onset cancers in adults based on (epi)genetic, biological, and environmental influences with an aim to motivate clinicians and scientists to think about these cancers from a broader perspective when developing their own research programs.

The management of advanced prostate cancer has evolved significantly with the advent of androgen receptor-targeted agents (ARTAs) and docetaxel, which now form the cornerstone of first-line systemic therapy in advanced disease. However, as increasing numbers of patients progress after exposure to both an ARTA and docetaxel, optimal treatment sequencing in the post-ARTA, post-docetaxel metastatic castration-resistant prostate cancer (mCRPC) setting remains an area of clinical uncertainty, with limited comparative data to guide decisions. This narrative review synthesises the current evidence surrounding treatment strategies for mCRPC in this later-line setting. Available therapeutic options include radioligand therapy (e.g. lutetium-177-PSMA-617), cabazitaxel, PARP inhibitors (particularly for patients with DNA repair gene alterations), second-line ARTAs, further chemotherapy and immunotherapeutic approaches. However, direct head-to-head trials comparing these modalities are sparse, and much of the available data comes from retrospective or subgroup analyses, necessitating a nuanced interpretation of outcomes and limitations. Beyond efficacy, this article emphasises the critical role of practical and individualised considerations in therapy selection. These include toxicity profiles, patient comorbidities and preferences, biomarker-driven stratification (e.g. BRCA status, PSMA expression, sites of metastases), and health system factors such as drug availability and reimbursement policies, which may significantly influence access to optimal care. Finally, the review provides an overview of promising emerging therapies poised to expand the treatment landscape for mCRPC. These include bispecific T cell engagers, androgen receptor degraders, and antibody-drug conjugates, which are currently under investigation in clinical trials and may soon offer new avenues for treatment beyond traditional mechanisms.

Introduction: This study aimed to assess the cost-effectiveness of neoadjuvant nivolumab + platinum doublet chemotherapy (PDC) versus relevant comparators in the treatment of patients with non-metastatic (stage IB-IIIA), resectable, non-small cell lung cancer (NSCLC) in England.

Methods: A four-state semi-Markov model (event-free survival, locoregional recurrence, distant metastasis, and death states) was developed. Key clinical inputs, including most transition probabilities and all health state utility inputs, were informed by data from the CheckMate-816 trial, which compared neoadjuvant nivolumab + PDC with neoadjuvant PDC. Neoadjuvant PDC, the trial comparator, is not typically used in England, so an indirect treatment comparison (ITC) estimated the relative efficacy of neoadjuvant nivolumab + PDC versus the relevant comparators. Comparators in the ITC and model were aligned with those suggested by the National Institute for Health and Care Excellence (NICE): neoadjuvant chemoradiotherapy, surgery alone, and surgery followed by adjuvant PDC. Costs were informed by standard UK sources. Cost and health outcomes were discounted by 3.5% per year.

Results: Over a lifetime time horizon, neoadjuvant nivolumab + PDC was dominant versus neoadjuvant chemoradiotherapy and adjuvant PDC, generating 0.26 and 0.7 incremental quality-adjusted life-years (QALYs) while reducing costs by £1674 and £240 per patient, respectively. Neoadjuvant nivolumab + PDC was more costly than surgery alone but was highly cost-effective; its estimated incremental cost-effectiveness ratio (ICER) was £2685 per QALY gained. Sensitivity and scenario analyses confirmed that these results are robust: only one of 10 scenarios tested yielded an ICER above £20,000 (the lower limit of the NICE reimbursement threshold).

Conclusion: Neoadjuvant nivolumab + PDC is a highly cost-effective treatment for nmNSCLC. The findings of this model supported positive reimbursement decisions for neoadjuvant nivolumab + PDC from NICE.

Introduction: Osimertinib is recommended, alongside afatinib, as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with atypical mutations in the epidermal growth factor receptor gene (EGFR), a population for whom real-world data are limited. We present outcomes and subsequent treatment patterns for this population in routine US practice.

Methods: Medical records from a manually curated oncology database were analyzed for adults with stage IIIB-IV NSCLC harboring atypical EGFR mutations, treated with first-line osimertinib (April 2018-March 2020). Data were analyzed overall and by EGFR mutation subgroups: compound EGFR mutations, comprising classical (exon [Ex] 19 deletion or L858R) and atypical (G719X, L861Q, S768I, E709X, Ex19 insertions, or Ex18-25 duplications) mutations or de novo T790M only (group A), and atypical EGFR mutations only (group B). Outcomes included real-world progression-free survival (rwPFS) and overall survival (OS).

Results: A total of 55 patients were included in the study (female 76%/male 24%; group A, n = 20; group B, n = 35). After a median follow-up of 11 months, median (95% confidence interval) rwPFS and OS, respectively, were 8.8 (5.5-17.2) and 28.5 months (11.4-41.8) overall, 20.3 (10.0-44.5) and 42.5 months (27.0-not estimable) in group A, and 6.6 (4.9-24.8) and 20.0 months (9.2-32.9) in group B. At follow-up, 13% of patients (n = 7) remained on first-line osimertinib (group A, 30%; group B, 3%), 54% (n = 30) had discontinued due to death (group A, 40%; group B, 63%), and 33% (n = 18) had received subsequent treatment (group A, 30%; group B, 34%), most commonly osimertinib combinations (28%; n = 5).

Conclusions: First-line osimertinib may provide real-world clinical benefits for patients with advanced NSCLC with atypical EGFR mutations, with results suggesting greater benefit in those harboring compound EGFR mutations.