Cancer Chemotherapy and Pharmacology最新文献

Background and aims: Trophoblast cell-surface antigen 2 (TROP2) is a cell surface glycoprotein that plays a significant role in the self-renewal, proliferation, invasion and transformation of tumor cells, and is highly expressed in a variety of tumors. At present, TROP2 has become an important target for the research and development of Antibody-drug conjugates (ADCs) in the field of lung cancer. Although sacituzumab govitecan, datopotamab deruxtecan and sacituzumab tirumotecan are all TROP2-targeted ADCs, there are certain differences in their drug structures. These differences may have led to the distinctions in their anti-tumor activity and safety. This study aims to review the similarities and differences among these three drugs, with the expectation of providing some assistance for the selection of clinical medication.

Methods: The key words Sacituzumab govitecan/IMMU-132, Datopotamab deruxtecan/DS-1062a and Sacituzumab tirumotecan/SKB264 retrieved Medline/PubMed, Google Scholar, Web of Science and ScienceDirect databases until September 25, 2025. Articles about pharmacokinetics, pharmacodynamics, drug safety and other aspects were selected to systematically summarize.

Results: These three TROP2 ADCs have many similarities in terms of pharmacokinetics, pharmacodynamics and common treatment-related adverse events. However, there are some differences in the efficacy of combination with immunotherapy drugs and treatment-related adverse events over grade 3.

Conclusion: There are differences in pharmacological effects, efficacy, and incidence of adverse events among sacituzumab govitecan, datopotamab deruxtecan, and sacituzumab tirumotecan. For patients with EGFR-mutated progression after targeted therapy or driver gene negative advanced non-small cell lung cancer, the individualized optimization of TROP2 ADCs treatment can obtain the greatest benefit.

Purpose: The combination of lazertinib and amivantamab has shown superior efficacy over first line osimertinib in EGFR-mutated metastatic non-small cell lung cancer, but is associated with significant toxicity and high costs. Lazertinib exposure varies widely due to genetic polymorphisms of the encoding for GSTM1, with almost 50% of Caucasians having a non-functional enzyme resulting in an approximate twofold higher systemic drug exposure. Despite this, all patients receive a fixed 240 mg once-daily dose irrespective of GSTM1 status, leading to avoidable toxicity without additional clinical benefit. Our purpose was to develop alternative dosing regimens based on GSTM1 status.

Methods: We conducted pharmacokinetic simulations using an existing validated population pharmacokinetic model to evaluate genotype-guided alternative dosing strategies in GSTM1 null individuals.

Results: Two regimens- 160 mg once daily (QD) and 240 mg every other day-were predicted to provide systemic exposures comparable to or exceeding those seen in GSTM1 non-null patients on the standard dose. The 160 mg QD dose resulted in a geometric mean ratio in GSTM1 null patients (GMR) for the trough (Ctrough) and average (Caverage) concentration relative tot he approved dose in GSTM1 non-null patients of 1.43 and 1.19, respectively. The respective GMRs for Ctrough and Caverage associated with 240 mg every-other-day dosing were 0.90 and 0.89, and this dosing regimen could reduce drug expenses up to 50% ($132.860 per year per patient) based on current pricing.

Conclusion: Our findings support the feasibility of individualized lazertinib dosing based on GSTM1 status to reduce toxicity and healthcare costs without compromising effective exposure.

Purpose: Tropomyosin receptor kinase (TRK) inhibitors have emerged as a promising class of targeted therapies for patients with tumors containing neurotrophic tyrosine receptor kinase (NTRK) gene fusions. While not noted in early clinical studies, about one-third of patients can experience diffuse arthralgias, myalgias, and allodynia in the contexts of missed, delayed, or discontinued therapy, resembling withdrawal-like symptoms. Here we report a case of a patient who had daily withdrawal-like symptoms which resolved after starting semaglutide.

Case presentation: A 35-year old male with metastatic/recurrent ETV6-NTRK3 fusion parotid gland cancer was enrolled on a clinical study investigating the efficacy of larotrectinib. He had a rapid complete response to therapy, and has continued on therapy for more than seven years. Early after starting therapy he experienced twice a day diffuse myalgias, arthralgias, and light sensitivity starting 30 to 45 min before his next dose was due. This continued until he was started on semaglutide, a GLP-1 receptor agonist, after which his symptoms completely resolved.

Conclusion: GLP-1 receptor agonists may have a role in improving side effects from larotrectinib. Possible mechanisms for this effect are discussed, with further research needed.

Background: High-dose chemotherapy (HDCT) combined with autologous stem cell transplantation (ASCT) rescue is an effective treatment option for relapsed or refractory germ-cell tumors. The TI-CE regimen, consisting of paclitaxel and ifosfamide for stem cell mobilization followed by high dose carboplatin and etoposide with ASCT rescue, is frequently used in the treatment of refractory disease. This regimen is challenging in patients who have undergone unilateral nephrectomy, since potential nephrotoxicity of ifosfamide poses a serious risk for permanent damage of the preserved kidney. Currently, the literature lacks data on the substitution of ifosfamide in the TI-CE regimen for an alternative chemotherapeutic agent with equivalent potency while being less nephrotoxic.

Case presentation: We present a case of a patient with refractory progressive metastatic germ-cell tumor who underwent nephrectomy and was successfully treated with a modified chemo-mobilization strategy. In the TI-CE protocol, ifosfamide was replaced for cyclophosphamide (TC-CE), resulting in a sufficient stem cell harvest through a single apheresis session. Post chemo-mobilization, LDH and hCG + hCGβ levels were normalized. Renal function remained stable throughout the course of treatment. Two months after HDCT, the patient showed a complete metabolic response, with no detectable tumor remnants. Currently, one year post-therapy, there are no signs of disease recurrence.

Conclusion: An effective and potentially less nephrotoxic chemo-mobilization regimen, using paclitaxel and cyclophosphamide (TC-CE), was administered to a patient with refractory metastatic germ-cell tumor who underwent HDCT followed by ASCT rescue after unilateral nephrectomy. Cyclophosphamide demonstrated to be a viable substitute for ifosfamide within the TI-CE regimen.

Mirdametinib is an MEK1/2 inhibitor having therapeutic potential for the treatment of neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PNs). NF1 is a rare and progressive genetic disorder. As a selective MAPK pathway modulator, it targets the dysregulated RAS (Rat Sarcoma viral oncogene homolog)/RAF (Rapidly Accelerated Fibrosarcoma)/MEK (Mitogen-activated protein kinase)/ (ERK) Extracellular signal-regulated kinase) signaling cascade, which plays a crucial role in NF1 tumor growth. PN, often progressive and disfiguring, significantly impairs quality of life (QOL), and it can transform into malignant peripheral nerve sheath tumors (MPNST). In February 2025, mirdametinib was FDA-approved under the brand name GOMEKLI for pediatric and adult patients with inoperable PNs.

Purpose: To evaluate the pharmacokinetic properties of UGN-102, a mitomycin-containing reverse thermal gel.

Methods: Twelve patients with NMIBC received 6 once-weekly intravesical instillations of UGN-102 (BL004: 120 mg mitomycin [n = 6]; BL005: 75 mg mitomycin [n = 6]). Plasma samples for determination of pharmacokinetic (PK) parameters were collected up to 6 h following instillation.

Results: In BL004, mean C_max was 20.39 ng/mL, and median was 16.10 ng/mL (range 4.00-40.40), 100-10-fold lower than reported myelosuppression toxic level (RMTL); and median T_max was 1.5 h. Mean AUC_0-6 was 56.23 ng·h/mL and mean apparent terminal half-life (t_1/2) was 49 min. The highest observed C_max (40.40 ng/mL) was 59-fold and 13-fold lower than C_max following IV 30 mg or 10 mg mitomycin, respectively, and 10-fold lower than the RMTL. Maximum measured urine concentration was 635 µg/mL. In BL005, mean C_max was 2.27 ng/mL, 181-fold lower than the RMTL; mean T_max was 1.95 h and mean AUC_0-6 was 5.69 ng·h/mL. At 4-6 h post intravesical instillation, mitomycin concentrations in urine were either below or approaching the lower level of quantification (< 0.250 µg/mL) in 5/6 patients. In the remaining patient, the measurable urine concentrations over the 6-hour period suggest dwell time was > 6 h post-instillation, possibly due to the tumor location restricting urine flow. However systemic exposure was < 4 ng/mL, 100-fold lower than the RMTL.

Conclusions: Intravesical instillation of UGN-102 results in low-level systemic absorption of mitomycin, with C_max values considerably lower than those following IV administration and those associated with myelosuppression.

Study registration: BL004: NCT02307487; BL005: NCT03558503.

Purpose: OX40 may stimulate T-cell activation, potentially enhanced with checkpointinhibition. Results are from the dose-escalation part of an ongoing, multicenter, open-label study (NCT04215978, registered 30 December 2019) investigating OX40 agonist BGB-A445 alone or with anti-PD-1 antibody tislelizumab in patients with advanced solid tumors.

Methods: Adults ≥18 years with previously treated advanced solid tumors, measurable by RECIST v1.1, enrolled. Dose-escalation A: 8 cohorts received increasing doses of IV BGB-A445 as monotherapy (20, 60, 150, 300, 600, 1200, 2400, 3600 mg); dose-escalation B: 6 cohorts received increasing doses of IV BGB-A445 (150, 300, 600, 1200, 2400, 3600 mg) + IV tislelizumab 200 mg. Primary objectives were safety and tolerability; secondary objectives included overall response rate (ORR) and pharmacokinetics.

Results: 112 patients were treated (A, n=63; B, n=49); 34/112 (30.4%) previously received checkpoint inhibitors. Treatment-related adverse events occurred in 36 (57.1%) (A) and 37 (75.5%) (B) patients, were grade ≥3 in 4 (6.3%) and 9 (18.4%), and caused treatment discontinuations in 1 (1.6%) and 1 (2.0%), respectively. Immune-mediated adverse events occurred in 8 (12.7%) (A) and 18 (36.7%) (B) patients, and infusion-related reactions in 9 (14.3%) (A) and 9 (18.4%) (B). No dose-limiting toxicities occurred. Unconfirmed ORR was 3.3% (unconfirmed partial response [PR], n=2) (A); confirmed was 21.3% (including PR, n=10) (B). BGB-A445 exposure increased dose-proportionally with a half-life of 8-13 days. OX40 receptor occupancy was saturated at ≥300 mg BGB-A445 in all cohorts.

Conclusion: BGB-A445 was well tolerated and demonstrated on-target immune activation at clinically relevant doses. Antitumor activity was observed across cohorts.

Purpose: Pediatric obesity is a growing public health concern, affecting drug pharmacokinetics, including chemotherapies. These challenges are amplified by the underrepresentation of children with obesity in clinical trials and the absence of clear dosing guidelines.

Methods: A retrospective, single-center cohort study was conducted at the Institute of Pediatric Hematology and Oncology (Lyon, France), including children with obesity (Body mass index > IOTF-30) treated with at least one intravenous chemotherapy between 2008 and 2022. Medical records were reviewed for patient characteristics, chemotherapy type, administered dose and adjustments. A literature review was performed using PubMed to evaluate chemotherapy dosing recommendations for children with obesity.

Results: A total of 248 chemotherapy courses for 113 children were analyzed, including 239 cytotoxic agents and 9 monoclonal antibodies. Most treatments were for hematological malignancies (n = 151), followed by solid tumors (n = 97). Only 45 chemotherapies (18%) were dose-adjusted in 19 patients (17%). Among these, 87% were capped at a body surface area (BSA) of 2 m², while 13% involved percentage-based reductions. Five adjustments were based on ideal body weight (IBW). Among the 25 patients with BSA > 2 m², 68% received adjusted doses, primarily through capping. In contrast, for patients with BSA < 2 m², dose reductions were rare and applied to avoid potential toxicity. The literature review revealed that total body weight (TBW) is generally used for dosing most chemotherapeutic agents, though certain drugs may require ideal body weight or adjusted body weight.

Conclusion: Heterogeneity in clinical practice reflects the absence of standardized pediatric guidelines. Therapeutic drug monitoring and further pharmacokinetic studies may further help optimize dosing. TBW is recommended based on the study results and literature review, with exceptions, and guidelines should be widely disseminated to improve clinical practice.

Background: Locally advanced oral squamous cell carcinoma (OSCC) is associated with poor survival outcomes, particularly in resource-limited settings, where treatment delays are prevalent. Oral metronomic chemotherapy (OMCT) utilising methotrexate and celecoxib is a potentially low-toxicity, cost-effective alternative in the neoadjuvant setting.

Methods: Thirteen patients diagnosed with stage 3 or 4 resectable OSCC were enrolled in this study. Each participant received one month of OMCT prior to surgical intervention and continued OMCT as maintenance therapy following treatment. The expression levels of PTGS2, VEGFA, VEGFB, KDR, CXCR1, and CXCR2 were analysed both before and after OMCT administration. Additionally, organ function and patient survival were evaluated to determine the efficacy and toxicity of treatment.

Results: PTGS2, VEGFA, VEGFB, and KDR were significantly upregulated in the tumour tissues at baseline. Post-OMCT, VEGFA, VEGFB, and KDR were significantly downregulated, whereas PTGS2 expression increased. No significant changes were observed in CXCR1 and CXCR2 expression. Liver, renal, and thyroid functions remained within normal limits. No adverse events were reported. The median overall survival was 22.1 months, and the median disease-free survival was 20 months. Upregulation of PTGS2, VEGFA, and VEGFB was correlated with improved outcomes.

Conclusion: OMCT has the potential to manage disease progression in patients with OSCC awaiting surgical intervention. It is characterised by low toxicity and may exert anti-angiogenic effects through modulation of the VEGF pathway. Further large-scale trials are necessary to substantiate these findings and to establish optimal treatment strategies.

Trial registration: The study was also registered in the Clinical Trials Registry of India (registration number: CTRI/2021/01/030256).