Targeted Oncology最新文献

Despite an evolving treatment landscape for people with metastatic castration-resistant prostate cancer, prognosis for this patient population remains poor. Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging may be used to identify patients with PSMA-positive (and no significant PSMA-negative) metastatic castration-resistant prostate cancer who could benefit from PSMA-targeted radioligand therapy. As the PSMA PET imaging and treatment landscape expands, there is a growing need for guidance and greater utilization of PSMA-targeted tracers and radioligand therapies to improve outcomes for patients with metastatic castration-resistant prostate cancer. This review discusses the current clinical considerations of PSMA PET, including the various imaging agents available and how best to identify patients eligible for PSMA PET imaging and subsequent PSMA-targeted radioligand therapy. This review also examines opportunities to mitigate discordant findings, as well as considerations around the standardization of reporting of PSMA PET imaging, key gaps in the evidence base, and guidance around the use of PSMA PET in clinical and research settings.

Background: Metastatic castration-resistant prostate cancer (mCRPC) presents a challenge for clinicians in determining the optimal treatment sequence because of the lack of direct head-to-head comparisons, which is further complicated by the now-widespread use of androgen receptor pathway inhibitors (ARPIs) in metastatic hormone-sensitive prostate cancer (mHSPC).

Objective: This study is a Bayesian network meta-analysis (NMA) intended to provide a comprehensive evaluation and comparison of the efficacy of mCRPC treatments across different treatment lines.

Patients and methods: We performed a systematic search of ClinicalTrials.gov, extracted information, assessed the risk of bias, and reconstructed missing outcomes. We performed an NMA to evaluate treatment efficacy for overall survival (OS) and progression-free survival (PFS) in first and subsequent lines. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines and was registered with PROSPERO (CRD42024499607).

Results: The NMA included 43 trials with 33,494 patients. ARPI-based therapies, particularly in combination with poly(ADP-ribose) polymerase inhibitors, demonstrated the most significant benefits for OS and PFS in first-line mCRPC treatment, followed by chemotherapy regimens. However, ARPI re-treatment showed limited effectiveness in subsequent lines, leading to weaker OS and PFS benefits.

Conclusions: This NMA highlights the superiority of ARPI-based therapies and chemotherapies as first-line options for mCRPC while emphasizing the need for treatment class switching after ARPI failure. To refine treatment sequencing and enable precision care, future research should integrate individual participant data to better address patient-level heterogeneity and identify biomarkers for personalized therapy.

Background: In the real-world POLARIS study, patients with hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) advanced/metastatic breast cancer (ABC) who had received palbociclib + endocrine therapy (ET) had a median real-world progression-free survival (rwPFS) of 20.9 months in the first line of therapy (1LOT) and 13.5 months in second or later LOTs (≥ 2LOT).

Objective: The aim of this study is to assess the relationship of prior anticancer treatments with clinical outcomes.

Patients and methods: Kaplan-Meier estimates of rwPFS and overall survival (OS) are described by prior anticancer treatments in patients with HR⁺/HER2^- ABC who received palbociclib + ET.

Results: A total of 1250 patients received ≥ 1 palbociclib dose (1LOT: 901 [72.1%]; ≥ 2LOT: 349 [27.9%]). In the 1LOT group, 563 (62.5%) had received prior (neo)adjuvant treatments: 24.3% ET alone, 26.6% chemotherapy alone, 45.5% ET + chemotherapy, and 3.6% other treatments; both median rwPFS and OS were numerically longer in patients who had received ET alone (30.4 months and not reached, respectively) and had had no prior treatment (23.7 and 53.3 months, respectively) than in patients with prior chemotherapy alone (15.9 and 38.4 months, respectively). In the ≥ 2LOT group, patients with prior ET alone (21.5%; 19.8 months) or chemotherapy alone (16.6%; 15.5 months) in the (neo)adjuvant and/or metastatic setting had numerically longer median rwPFS than those with prior ET + chemotherapy (41.3%; 11.6 months); OS was comparable regardless of prior treatment.

Conclusions: Patients with HR⁺/HER2^- ABC who had received ET alone prior to palbociclib tended to have better clinical outcomes, while those with prior chemotherapy had less clinical benefit.

Trial registration: ClinicalTrials.gov, NCT03280303.

Background: Based on the phase I/II MajesTEC-1 study, the B-cell maturation antigen (BCMA) and cluster of differentiation (CD)3 bispecific antibody, teclistamab, is approved for relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW), with the option to switch to 1.5 mg/kg every other week (Q2W) in patients maintaining complete response (CR) or better for ≥ 6 months on the QW schedule.

Objective: We report the pharmacokinetics (PK), pharmacodynamics, and anticancer activity of teclistamab 1.5 mg/kg Q2W, and the PK of teclistamab 3 mg/kg every 4 weeks (Q4W), on the basis of modeling and simulation results from MajesTEC-1.

Methods: Teclistamab PK was assessed using a population PK approach. Exposure-response analysis was based on individual estimated teclistamab serum trough concentration (C_trough). The impact of responders switching to Q2W teclistamab dosing on the formation of the key pharmacological species that drive the mechanism of action of teclistamab (i.e., the trimer formed by simultaneous engagement of teclistamab with BCMA on target multiple myeloma cells and CD3 on effector T cells) was estimated using a quantitative systems pharmacology (QSP) model. Additionally, steady-state teclistamab PK and trimer was simulated for the 1.5 mg/kg Q2W and Q4W (3 mg/kg or 1.5 mg/kg) doses.

Results: Median estimated teclistamab serum C_trough was lower after the first and fourth Q2W doses (14.4 and 11.7 µg/mL, respectively) than after QW doses (20.4 µg/mL) but remained above the 90% maximal effective concentration. No statistically significant exposure-response trend was observed for duration of response (DOR), progression-free survival, or overall survival in responders who switched to teclistamab 1.5 mg/kg Q2W dosing. Despite the lower teclistamab serum C_trough, the QSP model estimated comparable target cell-biologics-effector cell (TBE) trimer formation, tumor volume reduction, and DOR for responders switching to 1.5 mg/kg Q2W dosing versus not switching. Steady-state exposure metrics and trimer formation with teclistamab 3 mg/kg Q4W were estimated to be comparable with those at 1.5 mg/kg Q2W.

Conclusions: MajesTEC-1 modeling and simulation results, which contributed to the teclistamab label update, support the approved switch to teclistamab 1.5 mg/kg Q2W in patients maintaining ≥ CR for ≥ 6 months on the QW dose, without negatively impacting clinical efficacy. In addition, it is estimated that the 3 mg/kg Q4W schedule will provide maintenance of response comparable with the 1.5 mg/kg Q2W schedule. Teclistamab 3 mg/kg Q4W dosing will be evaluated in > 800 patients in three phase III studies in early line RRMM (MajesTEC-3, MajesTEC-9, and MonumenTAL-6) and in 100 patients in RRMM in the phase I MajesTEC-10 study.

Clinical trial registration: NCT03145181 (phase I,

Homologous recombination repair (HRR) gene alterations in prostate cancer predispose patients to more aggressive disease and a poorer prognosis. The presence of these HRR gene alterations may inform patient eligibility for clinical trials and targeted therapies, and importantly, through cascade testing, help identify family members at risk of developing an inherited cancer. This finding highlights the importance of testing for HRR gene alterations in patients with prostate cancer. Despite the potential implications of such testing to patient care, in a cross-sectional retrospective study in the USA, only 37.7% of patients with advanced prostate cancer underwent HRR testing between 2014 and 2022. The aim of this podcast is to identify obstacles to testing for HRR gene alterations that healthcare professionals encounter in day-to-day clinical practice, as well as discuss ways to potentially overcome them. In this multidisciplinary podcast, a genetic counselor, a medical oncologist, and a urologist discuss the importance of testing for HRR gene alterations and, using their different clinical perspectives, explore ways that healthcare professionals can integrate testing results into clinical practice.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment over the last decade, starting with the US Food and Drug Administration (FDA) approval of ipilimumab in 2011. Since that time, the FDA has approved nine additional ICIs, which now serve as frontline agents in lung, colorectal, head and neck, genitourinary, and skin cancers. ICIs have been practice-changing across many cancer subtypes, and their role in breast cancer (particularly in early-stage disease) is a topic of ongoing research. The only current FDA-approved ICI indication in early breast cancer is for the use of pembrolizumab in high-risk, triple-negative breast cancer in combination with chemotherapy, based on results from the KEYNOTE-522 trial. Although numerous trials have further investigated the use of ICIs in early-stage triple-negative breast cancer, survival outcomes have been inconsistent. Studies investigating the use of ICIs in early-stage estrogen receptor-positive and human epidermal growth factor receptor 2-positive breast cancer are even more limited, although available data (especially for estrogen receptor-positive disease) are promising. Numerous studies are ongoing, including critical investigations into biomarkers that may help determine which patients with breast cancer are most likely to benefit from the addition of immunotherapy. In this review, we discuss the history of ICI development, key trials investigating the use of ICIs in early-stage breast cancer, and future directions in the field.

Background: High-risk neuroblastoma (HR-NB) is associated with a poor prognosis. Standard first-line maintenance therapy with anti-disialoganglioside 2 (GD2) monoclonal antibodies, such as dinutuximab beta, has improved survival rates; however, approximately 50% of patients experience relapse and ~15% have disease that is refractory to induction therapy.

Objective: This systematic literature review aimed to evaluate response rates, survival outcomes, and safety in patients with relapsed or refractory (R/R) HR-NB receiving dinutuximab beta as maintenance therapy.

Patients and methods: We searched the PubMed, Embase, and Cochrane Library databases and regulatory reports from inception to 1 September 2024, and included studies of patients with R/R HR-NB in which dinutuximab beta (± isotretinoin) was used as maintenance therapy and that reported objective response or survival rates. Studies of dinutuximab beta plus chemotherapy combinations were excluded.

Results: We included nine publications/reports representing seven studies and 442 patients receiving dinutuximab beta. Across studies, the mean age was 5.1-6.4 years, and most patients were male. Reporting of response varied across studies between best response and end-of-treatment response. Best response rates with dinutuximab beta were 28.6-54.8%. All studies reported overall survival (OS), but follow-up times varied. Where reported, 3-year OS rates for patients receiving dinutuximab beta were 54-86% overall, with better OS rates reported for refractory than relapsed patients. Adverse events were frequent but manageable.

Conclusions: Maintenance therapy for patients with R/R HR-NB with dinutuximab beta as monotherapy or in combination with isotretinoin demonstrated efficacy and acceptable safety. Further studies are needed in patients previously treated with anti-GD2 therapies to evaluate efficacy and impact on target antigens.

Background: There are no studies that directly compare atezolizumab plus bevacizumab and tremelimumab plus durvalumab (STRIDE), two first-line options for the systemic therapy of advanced hepatocarcinoma (HCC).

Objective: We conducted a real-world retrospective analysis to compare the clinical efficacies of these two regimens.

Patients and methods: Using TriNetX data on patients with HCC at Barcelona Clinic Liver Cancer (BCLC) stages B or C, the analysis included patients treated with atezolizumab plus bevacizumab or with the STRIDE regimen. The primary endpoint was overall survival (OS) comparing the two treatment groups.

Results: Before applying propensity-score matching, a total of 2,307 consecutive patients were identified. Among them, 1,998 received atezolizumab plus bevacizumab, and 309 were treated with STRIDE. After matching, 618 patients remained, with 309 in each cohort. The analysis showed no significant difference between the two treatments: median OS was 15.4 months (95% confidence interval (CI) 14.7-51.6) and 15.5 months (95% CI 15.0-47.0) for patients treated with atezolizumab plus bevacizumab versus STRIDE, respectively (HR 0.94; 95% CI 0.73-1.22, p = 0.67). The univariate analyses of baseline clinical and laboratory characteristics indicated that the only differentiating factor between the two regimens was better survival for females receiving atezolizumab plus bevacizumab (HR 1.77; 95% CI 1.00-3.16, p = 0.04).

Conclusions: Atezolizumab plus bevacizumab and STRIDE demonstrated no statistical difference in OS, showing them to be equally valid alternatives for patients with advanced HCC.

Background: We developed, introduced, and evaluated Molecular ONcology Optimized CLinical Evaluation (MONOCLE), a secure, open-source web application at the University Medical Center Hamburg-Eppendorf (UKE), to optimize the analysis and discussion of complex cancer cases in molecular tumor boards (MTB).

Objective: MONOCLE standardizes and harmonizes documentation, while its integrated Knowledge Connector accelerates literature research for personalized treatment.

Patients and methods: The system was designed by merging the requirements of the German Network for Personalized Medicine (DNPM), the medical staff involved in the MTB process, and the team developing MONOCLE. The usability was evaluated using the System Usability Scale (SUS) and user tasks. Overall process optimization was measured by the number of automated tasks that can be performed.

Results: MONOCLE, introduced into clinical practice in June 2024, significantly reduces time for documentation, as three manual steps now run automatically, and transfer of the data to the DNPM is possible. Its usability and SUS showed positive results, ranging between 92.5 and 97.5.

Conclusions: As the first open-source and extendable solution for standardized MTB documentation, MONOCLE enables wider adoption by other medical centers.

Background: Tinurilimab is a humanized immunoglobulin G subclass 2 antibody that blocks carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), an immune checkpoint regulator that is overexpressed in several tumor types.

Objectives: This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and tumor response profile of tinurilimab in patients with advanced solid tumors with a described expression of CEACAM6.

Patients and methods: In this first-in-human, dose-escalation and dose-expansion study, tinurilimab was administered as a 1-h intravenous infusion in 21-day cycles at a starting dose of 2.5 mg, with a planned escalation up to 1800 mg. Following observation of treatment toxicity (cytokine release syndrome in one patient and neutropenia in all patients treated at 30 mg), a premedication regimen was initiated that included dexamethasone 8 mg before and after dosing. Thirty patients received treatment across six dosing cohorts (2.5-100 mg with or without dexamethasone).

Results: The maximum tolerated dose was not determined, as the study was terminated due to an unfavorable benefit/risk assessment. All 30 patients (100%) treated with tinurilimab experienced at least one treatment-emergent adverse event of any grade, most commonly fatigue (36.7%), infusion-related reaction (30.0%), and neutropenia (26.7%). The most common grade ≥ 3 treatment-related adverse events were neutropenia (23.3%), followed by febrile neutropenia, cytokine release syndrome, increased hepatic enzymes, decreased lymphocyte count, hypophosphatemia, lactic acidosis, and acute kidney injury (3.3% each). No patients reported an objective response.

Conclusions: Following study termination, the clinical development program for tinurilimab was discontinued permanently.

Clinical trial registration: www.

Clinicaltrials: gov , NCT03596372.