BACKGROUND:Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS:This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS:Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION:Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Background The incidence of non-small cell lung cancer (NSCLC) is increasing in women, including those of childbearing age. While recent drugs such as osimertinib and alectinib have improved the prognosis of specific molecular subtypes (e.g., EGFR-mutant and ALK-rearranged NSCLC), their potential use during pregnancy remains inadequately supported by pharmacological data. Objective To assess the transplacental transfer and placental cotyledon accumulation of osimertinib and alectinib, using a human ex vivo placental perfusion model. Study design Term placentas from normal pregnancies were collected after delivery and perfused with osimertinib or alectinib (in combination with alectinib major active metabolite M4) doses simulating steady state plasma concentrations observed in maternal plasma. Fetal transfer rate, clearance index, and cotyledon accumulation were evaluated, with antipyrine used as a control marker. Samples were collected during a 90-min procedure. Results Significant transplacental transfer of osimertinib was observed, with a fetal transfer rate of 9.5% and a CI of 0.41, and cotyledon accumulation of 28.9%. In contrast, neither alectinib nor M4 were detected in fetal samples, although both were found to accumulate substantially in placental tissues (370.7% and 178.3%, respectively). Conclusion These findings suggest that osimertinib crosses the placenta with a moderate tissue uptake, while alectinib and its metabolite M4 do not appear to be transferred to the fetus but accumulate significantly within the placental tissue. Further studies are needed to guide treatment selection for NSCLC in pregnant women.

Systemic treatment received by patients prior to selective FGFR inhibitors, according to the detection of FGFR kinase domain mutations and/or PI3K/mTOR pathway alterations.

Expression of FGFR3:TACC3 was homogeneous across Ba/F3 cell lines.

IC50 values of Ba/F3 cells harboring FGFR3:TACC3 mutants exposed to eight selective FGFR inhibitors.

Patient population, treatment outcomes and post-progression sample availability.

Documentation of the allelic status in cis of FGFR3 S249C and V553L mutations from MR406 tissue biopsy.

Acquisition of mutations in PI3K/TSC1 pathway at progression to FGFR inhibitors.

Synergic effect of gefitinib and erdafitinib in MR15 cell line.

Background Nivolumab is an immune checkpoint inhibitor (ICI) that selectively inhibits programmed cell death protein 1 activation, restoring antitumor immunity. ICIs are indicated for various types of advanced solid tumors; however, not all patients benefit from them, and tools that could be used in the clinic to predict response to treatment represent an unmet need. Here we describe the development of a new population pharmacokinetic (PPK) model in patients treated with nivolumab in clinical trials. Applying the model to a patient population with renal cell carcinoma identified nivolumab clearance and plasma concentration as predictors of overall survival (OS).Methods A custom liquid chromatography with tandem mass spectrometry method for quantifying nivolumab plasma concentration was developed and validated following the European Medicines Agency guidelines for bioanalytical method validation. The PPK model was developed using data from patients treated in the NIVIPIT (n=38) and NIVOREN (n=137) trials of nivolumab in metastatic melanoma and renal cell carcinoma, respectively. The PPK model was used to determine pharmacokinetic (PK) parameters such as baseline clearance and simulate individual clearance changes over time. The relationship between PK characteristics (including clearance at Cycle 1 (CLC1), plasma concentration at Cycle 3 and clinical outcomes was assessed in 137 patients treated in NIVOREN. Kaplan-Meier methodology was used in time-to-event analyses.Results In 137 patients, the median nivolumab CLC1 was 6 mL/hour and the median plasma concentration at Cycle 3 was 48 µg/mL. Median follow-up was 21.0 months (95% CI 20.2 to 22.5 months) with a survival rate at 6 months of 91.2% and 77.9% at 12 months. In univariate analysis, OS was significantly higher in patients with CLC1<6 mL/hour versus ≥6 mL/hour (HR 2.2 (95% CI 1.2 to 4.1), p=0.0146). Shorter OS was observed in patients with plasma concentration at Cycle 3 below the median (48 µg/mL) versus those above the median (HR 0.4 (95% CI 0.2 to 0.8), p=0.0069). Multivariate analysis showed a trend towards lower clearance, but this did not reach statistical significance (p=0.0694).Conclusions Results of the study may potentially be used to predict outcomes of nivolumab therapy in patients with renal cell carcinoma. Additional applications may include guiding dose adjustments of nivolumab in those who are less likely to respond to the initial dose.

RNAseq analysis from tissue biopsies of 39 advanced urothelial cancers.

Context:Mucopolysaccharidosis (MPS) requires urgent treatment to prevent neurological damage. While gene therapy holds promise for effectively treating these diseases with minimal toxicity, access remains limited for most patients. Consequently, advancing allogeneic hematopoietic stem cell transplantation (HSCT) for young children is crucial. Since the 2010s, cord blood (CB) transplants with reduced-toxicity conditioning (RTC) have become the standard of care. Patients and methods:Recent reports in France indicate a significant incidence of graft failures (GF), prompting a large-scale retrospective study from the French-speaking bone marrow transplantation society's registry, to understand GF risks, guide clinicians in selecting transplant platforms, and describe outcomes of second HSCT in young patients. Results:This report analyses 93 children who underwent HSCT for MPS between 2000 and 2020. The GF rate was notably high (22.6% at day 100), primarily associated with the donor's HLA compatibility and the recipient's age. Well-matched CB and RTC were not found to be risk factors for GF. This study also details the procedures for second and third transplants in patients who rejected their first HSCT. Conclusion:In the era of RTC, CB remains a viable and expedient option for MPS transplantation.

Outcomes among patients suffering from intrahepatic cholangiocarcinoma, treated with either reversible FGFR inhibitors or the irreversible agent futibatinib.

Tumor types, FGFR2 drivers, and clinical outcomes of patients suffering from tumors other than intrahepatic cholangiocarcinoma, treated with selective FGFR inhibitors.

ContextObesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes.ObjectivesTo summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients.MethodsWe conducted a systematic review that included all pharmacological studies published after 2000.ResultsUnexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy.ConclusionsCaution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed.

Real-life populations are more heterogeneous than those included in prospective clinical studies. In cancer patients, comorbidities and co-medications favor the appearance of severe adverse effects which can significantly impact quality of life and treatment effectiveness. Most of tyrosine kinase inhibitors (TKI) have been developed with flat oral dosing exposing patients to the risk of poor adherence due to side effects. Additionally, genetic or physiological factors, differences in diet, and drug-drug interactions can lead to inter-individual variability affecting treatment outcomes and increasing the risk of adverse events. Knowledge of the different factors of variability allows individualized patient management. This review examines the effects of adherence, food intake, and pharmaceutical form on the pharmacokinetics of oral TKI, as well as evaluating pharmacokinetics considerations improving TKI management. Concentration-effectiveness and concentration-toxicity data are presented for the selected TKI, and a simple therapeutic drug monitoring schema is outlined to help individualize dosing of oral TKI.

Specific FGFR2 drivers of the 27 patients suffering from intrahepatic cholangiocarcinoma.

Graphical representation of the IC50 values of reversible (A) and irreversible (B) inhibitors in parental and FGFR2::BICC1 Ba/F3 mutants.

Clinico-radiological and molecular evolution of patient MR553, suffering from a FGFR2-rearranged intrahepatic cholangiocarcinoma.

Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco-hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure-response relationship), and safety (maximum tolerated dose, and exposure-safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco-hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score.