Drug-related Toxicity Research Articles

The role of body composition in neurological and hematologic toxicity in a retrospective analysis of 120 breast cancer patients undergoing neoadjuvant chemotherapy: the COMBOTOX study.

Neoadjuvant chemotherapy (NAC) has a well-established role in locally advanced or chemoresponsive breast cancers (BC). Chemotherapic regimens are effective when patients receive the optimal doses. Toxicities are common in overweight/obese patients but may occur also in normal weight counterparts. This leads to delays, reductions, or discontinuation of treatment, with impact on outcomes. Current dosing is based on body weight and predicted Body Surface Area (BSA). These parameters do not take into consideration the individual variations of fat mass (FM) and fat-free mass (FFM) that affect pharmacokinetics. Assessment of body composition (BoCo), rather than Body Mass Index (BMI), could help to better plan chemotherapy and reduce drug-related toxicities. Our aim was to analyze the correlations between body weight, anthropometric measures, BoCO, and toxicities related to NAC in non-metastatic BC patients. This is a retrospective observational cohort study that includes 120 consecutive BC patients undergoing NAC, enrolled between May 2018 and December 2020. All patients received an evaluation of anthropometric parameters (height, weight, waist and hip circumference, BMI) and an assessment of BoCo using Segmental Multi-Frequency-Bioelectrical Impedance Analysis. A logistic regression models confirmed that a higher FM was associated with a higher rate of neurological and hematologic toxicities in protocols containing Platinum. Moreover, patients with a low FFM% have a higher risk for hematologic toxicity in protocols containing Platinum. A routine assessment of BoCo, in addition to evaluation of anthropometric measures and BMI, could allow to personalize chemotherapy doses, in order to reduce chemotherapy-related toxicities.

Mimickers of hydroxychloroquine retinal toxicity.

Hydroxychloroquine (HCQ) retinal toxicity is an important entity that can be challenging to differentiate from its mimickers. Bull's eye maculopathy is the classical presentation of HCQ retinopathy; however, its differential includes several drug-related retinal toxicities, inherited retinal disorders, and systemic conditions with associated retinopathies. Given the similarities in clinical presentation, imaging findings, and other diagnostic data, it can be quite challenging for all but the retina specialists to successfully identify retinal toxicity from HCQ. This review summarises HCQ retinopathy and its mimickers of with a special emphasis on key clinical and ancillary distinctions that can help comprehensive ophthalmologists and primary care offices in clenching this diagnosis.

Sex and common germline variants impact the toxicity profile and pharmacokinetics of alectinib: a nation-wide cohort study in patients with ALK-positive non-small cell lung cancer

IntroductionAlectinib, a small-molecule kinase inhibitor, is used as first-line treatment for anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC). Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity. MethodsIn this multicenter observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in ABCB1, CYP3A4, PPAR-α, POR, and CYP3A5. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals. ResultsAmong 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p=0.001) and also had +35% higher alectinib trough levels (p<0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade ≥ 3 toxicity (38%) compared to patients who carried at least one wild-type allele (11%) (p=0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95%CI: 2.9–36.6%; p=0.019) higher trough levels. ConclusionsFemale patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pre-treatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.

Abstract 4126893: Feasibility and Acceptability of a Nurse-Pharmacist Post-Discharge Telehealth Model of Care for Heart Failure Patients

Background: Suboptimal medication management is common in patients with heart failure (HF), particularly during transitions-of-care. To date, there are few studies assessing the feasibility of a nurse-pharmacist post-discharge telehealth service for medication optimisation in patients with HF. We performed a feasibility study to determine service uptake and acceptability, and ability to identify medication-related issues for HF patients as they transition from hospital to home. Methods: HF patients were referred to an existing post-discharge telehealth service and offered medication reconciliation and education in addition to their usual care; a service we termed ‘MedRec’ (MR). Primary outcomes were feasibility, measured through recruitment and successful MR completion, and acceptability, measured by an investigator-developed survey. Secondary outcomes were medication-related issues detected during MR. Results: A total of 100 HF patients were offered a post-discharge MR. Mean age of patients was 68.5 ±14.2 years, and mostly male sex (62%). Pharmacist MRs were requested by 80% of patients. In total 62 MRs (77.5%) were performed; 9 patients declined MR during follow-up and an additional 9 patients were uncontactable. Mean time to MR following nurse referral was 10.98 ±9.74 days. Drug-related toxicity or adverse effect presentation was identified in 25 (40.3%) MR recipients at the time of consultation and subsequently required general practitioner follow-up. Medication compliance issues were detected by the pharmacist in 13 (20.9%) patients; forgotten doses being the most common concern. Undertreated medical conditions, such as symptomatic HF and chronic pain, were identified in 12 (19.3%) MR recipients. Medications prescribed without any apparent indication were found in 8 (12.9%) patients. Drug or disease management information was requested by 35 (56.4%) MR recipients. A total of 35 (56.5%) post-MR surveys were successfully completed. All participants who completed a post-MR survey agreed that a post-discharge telehealth MR was an acceptable form of education provision. Engagement with a pharmacist MR was perceived to ease anxiety associated with understanding medication-related changes and empowered greater medication self-management. Conclusions: A post-discharge nurse-pharmacist telehealth service is a feasible and acceptable model of care. Inclusion of a routine MR post-discharge may be an effective means of maintaining continuity of care for HF patients.

Profiling the gut and oral microbiota of hormone receptor-positive, HER2-negative metastatic breast cancer patients receiving pembrolizumab and eribulin

Aim: Changes in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. In the KELLY phase II study (NCT03222856), we previously demonstrated that pembrolizumab [anti-programmed cell death protein 1 (PD-1)] combined with eribulin (plus microtubule-targeting chemotherapy) showed encouraging antitumor activity in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) who had received prior treatments. Methods: A total of 58 fecal and 67 saliva samples were prospectively collected from a subset of 28 patients at baseline (BL), after three treatment cycles, and end of treatment. Shotgun metagenomics, 16S rRNA gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize fecal and oral microbiota profiles. Results: Treatment caused no substantial perturbations in gut or oral microbiota, suggesting minimal drug-related microbial toxicity. Bacteroides and Faecalibacterium were the dominant gut microbiota genera, while Prevotella and Streptococcus were present in both oral and gut samples, highlighting potential gut-oral microbial interactions. Additionally, clinical benefit (CB) appeared to be associated with gut-associated Bacteroides fragilis (B. fragilis ) and a BL oral abundance of Streptococcus ≥ 30%. Notably, B. fragilis NCTC 9343 supernatant induced dose-dependent lactate dehydrogenase (LDH) release from the MCF-7 (HR-positive/HER2-negative) BC cell line. Conclusion: These findings suggest that specific gut and oral microbiota may modulate the effectiveness of combinatory anti-BC therapies, potentially through the action of microbial metabolites.

Risk and Benefit for Basket Trials in Oncology: A Systematic Review and Meta-Analysis.

Oncology research is increasingly adopting new clinical trial models that implement the concept of precision medicine. One of these is the basket clinical trial design. Basket clinical trials allow new treatments to be evaluated across multiple tumor types. Patients recruited to basket clinical trials share certain molecular characteristics of their cancer that are predictive of clinical benefit from the experimental treatment. Our aim was to describe the risks and benefits of basket clinical trials in oncology. Our study was prospectively registered in PROSPERO (CRD42023406401). We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of basket clinical trials in oncology published between 1 January, 2001, and 14 June, 2023. We measured the risk by treatment-related adverse events (grades 3, 4, and 5), and the benefit by objective response rate. We also extracted and analyzed data on progression-free survival and overall survival. When possible, data were meta-analyzed. We included 126 arms of 75 basket clinical trials accounting for 7659 patients. The pooled objective response rate was 18.0% (95% confidence interval [CI] 14.8-21.1). The rate of treatment-related death was 0.7% (95% CI 0.4-1.0), while 30.4% (95% CI 24.2-36.7) of patients experienced grade 3/4 drug-related toxicity. The median progression-free survival was 3.1 months (95% CI 2.6-3.9), and the median overall survival was 8.9 months (95% CI 6.7-10.2). Our results provide an empirical basis for communicating about the risks and benefits of basket clinical trials and for refining new models of clinical trials applied in precision medicine.

Colorectal cancer research priorities in Uganda: perspectives from local key experts and stakeholders.

The incidence of colorectal cancer (CRC) is increasing in Uganda but there is limited local research to guide policy and programming for CRC prevention and control. A stakeholder engagement workshop took place in Kampala on 19March 2024 to identify challenges and opportunities for CRC prevention and control in Uganda. A total of 30 stakeholders with expertise in CRC primary and secondary prevention, diagnosis, treatment, palliative care as well as cancer survivors participated in the workshop. Key challenges for primary prevention included low knowledge/awareness of CRC among the general population and health workers, and rising prevalence of CRC related risk factors. Limited CRC screening, diagnostic facilities and specialists were identified as barriers to diagnosis. Treatment related challenges included limited accessibility to surgical services and drugs, late-stage presentation leading to poor treatment response, treatment abandonment and drug related toxicity. Lack of universal health coverage policies, limited community-based cancer awareness programs, and lack of national cancer registries were cited as policy and economics challenges. Opportunities to address these challenges were discussed. Our findings highlight areas for further research and prioritization to address Uganda's growing CRC burden and may be applicable to other low-resource settings.

The impact of inter-cycle treatment delays on overall survival in patients with advanced-stage ovarian cancer.

Chemotherapy forms the cornerstone of systemic treatment for advanced ovarian cancer, extending overall survival; however, drug-related toxicity can lead to treatment delays, potentially diminishing treatment efficacy. This study evaluated the impact of treatment delays on all-cause mortality of patients with ovarian cancer, to better inform decisions on patient management. This retrospective, population-based cohort study included 1517 women with advanced-stage ovarian cancer, receiving first-line adjuvant or neoadjuvant chemotherapy in 2014 and 2015. The frequency of inter-cycle delays >7 dayswas calculated using drug administration dates. Kaplan-Meier estimates were used to compare 2-year overall survival (OS) between patients who were delayed and those treated to schedule. Cox proportional hazards regression was used to investigate the impact of treatment delay on all-cause mortality. Inverse probability of treatment weighting propensity scores were used to adjust for confounding variables. Delays >7 days occurred in 35.3% of patients. Two-year OS probability was 62.7% in patients who experienced treatment delays >7 days (95% CI, 58.7-66.9) compared to 69.1% in those treated to schedule (95% CI, 66.2-72.0). Delays were not significantly associated with all-cause mortality when adjusted for confounders (HR 1.00 95% CI, 0.83-1.20, P = .9). Delays to chemotherapy treatment were not significantly associated with worsened survival in patients with advanced-stage ovarian cancer. These results can inform clinical decision making that prioritize toxicity management and quality of life for those treated with chemotherapy.

Novel harm reduction measures at music festivals in Australia: Pilot implementation of the Emerging Drugs Network of Australia-Victoria toxicosurveillance methodology.

Harm reduction strategies at music festivals seek to create a safer environment for patrons. The Emerging Drugs Network of Australia-Victoria (EDNAV) project is a state-wide toxicosurveillance network that derives drug intelligence from a sample of patients presenting to hospital with illicit drug-related toxicity. This publication describes the preliminary outcomes of conducting toxicosurveillance for critically unwell festival patrons within on-site medical facilities. Blood samples were collected from patrons who presented with severe illicit drug-related toxicity across three festivals (2022/2023). Blood samples were analysed via liquid chromatography-tandem mass spectrometry for over 700 pharmaceutical and illicit drugs. There were 1603 individual medical encounters across the festivals, 228 of which were illicit drug related. A blood sample was collected for 24 patients, with a median age of 22 years (range 18-39 years). A median of two drugs (range 1-5 drugs) were reported and four drugs (range 0-8 drugs) were analytically confirmed per patient. The most frequently reported exposures were congruent with analytical results, 3,4-methylenedioxymethamphetamine (reported n = 17, detected n = 20), ketamine (reported n = 9, detected n = 13) and cocaine (reported n = 9, detected n = 12). An unreported illicit drug and/or new psychoactive substance (NPS) was detected in 18 patients, including methylamphetamine (n = 10), a cathinone (n = 7), benzodiazepine-type NPS (n = 6), N-ethylamphetamine (n = 1), 3-hydroxyphencyclidine (n = 1) and/or 4-hydroxy-N-methyl-N-isopropyltryptamine (n = 1). EDNAV toxicosurveillance serves as an additional tool within a multi-faceted approach to harm reduction at festivals. Continued data collection will allow for the characterisation of high-risk drug use patterns to provide evidence-based messaging to festival patrons and key stakeholders.

A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

An update on the status of HSP90 inhibitors in cancer clinical trials.

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60% have been completed, 10% are currently active, and 30% have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

DRUGS SAFETY IN CHILDREN

Background: There is a need to promote drug-related safety in children and prevent them from drug-related toxicities. Understanding pediatric pharmacology, drug dosing, and physiological differences between children and adults is crucial for ensuring safe and effective pediatric care. Objectives: The focus of the current review is the safety and efficacy of drugs in children that involve medication errors and adverse drug reactions. The present study includes awareness of past medication-related incidents, off-label drug usage, inappropriate antibiotic prescriptions, adverse reactions to over-the-counter drugs, and cases of pharmaceutical poisoning in children. Methodology: Pertinent literature databases from search engines like Google Scholar and PubMed were retrieved and analyzed, and WHO and FDA guidelines were followed. Results: The literature survey showed that these problems can be overcome by taking safety measures and following evidence-based practice recommended by the FDA, reducing dosing errors, and preventing ADRs. The Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) has made efforts in conducting drug research and improving pediatric labelling. Conclusion: A warning showing more recent information about contraindications must be mentioned in pharmaceutical labelling so the patient and doctors would be better aware of drug contraindications and their adverse effects.

Multicenter Analysis of Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients.

Valganciclovir is the only approved antiviral for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation (SOT). Additional approaches may be needed to improve outcomes. A multicenter retrospective study from 2016 to 2019 was conducted of pediatric SOT recipients in whom at least 3 months of valganciclovir prophylaxis was planned. Episodes of CMV DNA in blood (DNAemia), CMV disease, drug-related toxicities, as well as other infections in the first year posttransplant and demographic and clinical data were collected. CMV DNAemia in the first year after prophylaxis or during prophylaxis (breakthrough) was analyzed by multivariate hazard models. Among the 749 patients enrolled, 131 (17.5%) had CMV DNAemia at any time in the first year; 85 (11.4%) had breakthrough DNAemia, and 46 (6.1%) had DNAemia after prophylaxis. CMV disease occurred in 30 (4%). In a multivariate model, liver transplantation compared to kidney or heart, intermediate or high risk based on donor/recipient serologies, neutropenia, and valganciclovir dose modifications attributed to toxicity were associated with increased risk of total and/or breakthrough DNAemia. Bacteremia was also associated with increased hazard ratio for CMV DNAemia. In a separate multivariate analysis, rejection occurred more often in those with breakthrough CMV DNAemia (P = .002); liver transplants, specifically, had increased rejection if CMV DNAemia occurred in the first year (P = .004). These associations may be bidirectional as rejection may contribute to infection risk. CMV DNAemia in the first year posttransplantation occurs despite valganciclovir prophylaxis and is associated with medication toxicity, bacteremia, and rejection. Pediatric studies of newer antivirals, especially in higher-risk subpopulations, appear to be warranted.

NFS-11. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

Abstract BACKGROUND Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS). METHODS Eligible participants were age &amp;gt;5 years with a clinical diagnosis of neurofibromatosis type 2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL). RESULTS Twelve participants were enrolled and eight completed 12 cycles, including two pediatric patients. Two patients were non-evaluable due to coming off study prior to the first scheduled response evaluation: one withdrew from the study for personal reasons and one for non-compliance. Due to slowing accrual, the study closed prior to meeting planned enrollment of 17 evaluable patients. Ten patients were evaluable for the primary endpoint, defined as ≥20% decrease in VS volume, with two volumetric responses observed; both were reached after three cycles and sustained during treatment. Best volumetric response was −53.9% after nine cycles. Hearing response was evaluable in nine participants, with three hearing responses observed, one of which was sustained during treatment. All participants experienced drug-related toxicities, the most common were diarrhea, hematuria and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment in all participants. CONCLUSIONS Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. The convenience of oral administration appears to be offset, however, by increased toxicity and lower response rates compared to VEGF-A targeted therapy with bevacizumab.

Interim safety and efficacy of BP1001 in a phase II acute myeloid leukemia (AML) study.

6511 Background: Oncogenic tyrosine kinases induce AML progression via the growth factor receptor bound protein-2 (Grb2). BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and venetoclax (VEN). A multi-center open-label Phase II study was initiated to assess whether the BP1001 + DEC + VEN combination provides higher response rates than historically reported responses of DEC + VEN in newly diagnosed AML (including secondary AML) (cohort 1) or refractory/relapsed (R/R; cohort 2) AML patients (pts) considered unsuitable for intensive chemotherapy. Per protocol, when 19 evaluable pts are enrolled in each cohort, interim analysis will be performed to determine which cohort has ≥5 complete responses and will continue with enrollment. Methods: BP1001 was given, beginning on Day 4, at 60 mg/m2 IV, 2x weekly for a total of 8 doses over a 28-day cycle. DEC was given IV on days 1 to 5 at 20 mg/m2. VEN was given PO at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Interim analysis was performed on Jan 24, 2024 on pts enrolled between July 28, 2020 and December 26, 2023. Evaluability for efficacy was defined as: completion of at least 4 cycles of combination therapy, documented Progressive Disease (PD) or any drug toxicity at any time, or CR/CRi/CRh prior to 4 cycles. Results: In Cohort 1, 31 newly diagnosed pts were enrolled; 20 evaluable pts (9 male: 45%) with a median age of 75 years (range, 69 - 84), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=12, ELN 2017 classification) or secondary AML (sAML; n=7) evolved from MDS (n=4), CMML (n=1) or treatment-related AML (n=2). Fifteen pts (75% of evaluable; 54% of enrolled) achieved CR/CRi/CRh; 2 pts achieved partial remission (PR) and 2 achieved stable disease (SD). In Cohort 2, 38 R/R pts were enrolled; 23 evaluable pts (13 male: 57%) with a median age of 63 years (range, 24 - 89), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=13) or sAML (n=5). Twelve pts (55% of evaluable; 32% of enrolled) achieved CR/CRi/CRh; 1 pt achieved PR, 8 achieved SD and 1 had treatment failure. Among the evaluable pts of both cohorts, adverse events were consistent with those expected with DEC, VEN and/or AML, including fatigue (72%), anemia (60%) and neutropenia (49%), while the most frequent serious adverse events were febrile neutropenia (26%) and sepsis (5%). Conclusions: BP1001 + DEC + VEN has been safely administered to pts without drug-related toxicity. Since &gt;5 responses are observed in both cohorts, the study will continue with enrollment up to 98 and 54 evaluable pts in cohorts 1 and 2, respectively. Efficacy data are encouraging in a challenging population of frontline adverse-risk, sAML and R/R pts. Clinical trial information: NCT02781883 .

Relationship of body mass index and plasma imatinib levels in CML patients and mitigation of clinical impact using PK-guided dosing strategy.

e18522 Background: Imatinib is a mainstay of treatment for patients with chronic myeloid lymphoma (CML). Exposure-response relationships have been demonstrated and trough levels between 800 and 1000 ng/ml are usually associated with Major Molecular Response (MMR), prolonged survival and acceptable safety. The extent to which body mass index (BMI) might influence drug pharmacokinetics (PK) and clinical outcome remains to be investigated. Methods: Therapeutic drug monitoring was performed in 60 adult patients (56 years, M33/27F) starting imatinib (400 mg QD) for CML, and baseline deviation from target Cmin was used to subsequently adjust dosing using Monolix software. Baseline BMI was calculated and collected along with other patient characteristics and comedications likely to alter imatinib PK. Response (MMR at 3 months) and drug-related toxicity (CTCAE grading) were recorded. Patients were divided into three subgroups: BMI&lt;18.5; 18.5&lt;BMI&lt;24.5, and BMI&gt;24.5. The association between BMI and trough imatinib levels at baseline, further differences in toxic events and response rate between cohorts, as well as differences in dosing after PK-guided dose adjustment, were all tested using appropriate statistical analysis. Results: Mean imatinib trough levels at baseline were 1172 (754-4737), 870 (276-1767) and 820 (334-2217) ng/ml for patients with BMI&lt;18.5, 18.5&lt;BMI&lt;24.5 and BMI&gt;24.5, respectively. Patients with BMI&lt;18.5 were statistically overexposed (p&lt;0.01, ANOVA). Conversely, there was a trend towards lower exposure in patients with BMI&gt;24.5, but this was not statistically significant. Multivariate analysis confirmed that low BMI was an independent factor for overexposure with imatinib. After PK-guided dosing, a statistically significant difference in dosing after correction was observed, as overexposed patients had their dose reduced to an average of 330 mg QD, whereas underexposed patients had their dose increased to an average of 500 mg QD (p&lt;0.01, paired t-test). Consequently, when comparing in the three different cohorts the incidence of both response and toxic events, no difference was observed among patients (p=0.33 and p=0.911 for efficacy and toxicity respectively, Chi-2 test). Conclusions: Low BMI (&lt;18.5) puts patients at risk of significant overexposure to imatinib, whereas there is a trend towards lower exposure in patients with high BMI (&gt;24.5). This could potentially lead to either increased toxicity or lack of efficacy is no adjustment in dosing is performed. Here, TDM with subsequent adaptive dosing helps to correct the dose according to the initial deviation from target, thus smoothing the clinical impact of the differences in exposure observed at the start of treatment.

ImmunoSarc II master trial (phase II of sunitinib and nivolumab): Results from the dedifferentiated chondrosarcoma (DDCS) cohort—A GEIS, ISG and UCL study.

11506 Background: Dedifferentiated chondrosarcoma (DDCS) is a rare aggressive CS subtype with a dismal prognosis and no standard of care systemic therapy. For those with advanced, metastatic disease, retrospective chemotherapy studies demonstrate short-term median progression-free survival (PFS) of around 3 to 5.5 months. Benefit from checkpoint and tyrosine kinase inhibitors has been reported, however clinical trial data is scarce, and endpoints are not well defined, thus benchmarking outcomes is challenging. The IMMUNOSARC I master-trial exploring sunitinib plus nivolumab in multiple sarcoma subtypes, detected potential activity in DDCS leading to a specific cohort within the phase II trial IMMUNOSARC II (NCT03277924). Methods: Patients (pts) with ECOG 0-1, centrally confirmed and progressive, measurable DDCS were eligible and treated with sunitinib 37.5 mg/d for 14 days (induction phase), followed by 25 mg/d, in combination with nivolumab 240 mg every 2 weeks until progressive disease (PD) or intolerance. Imaging assessments were performed every 8 weeks. Main endpoint was 6-m PFSR with one-arm survival design (type I error α 0.05, power 0.90, H0 40%, H1 70%) and a Brookmeyer-Crowley like test was assumed with at least 14 of 23 pts required without progression at 6 months. Results: Between December 2019 and October 2023, 24 pts with a median age of 60 years (38-76) were enrolled in 7 centres. Sixteen pts (66%), were male. Pts had received a median of 1 (0-2) prior lines of therapy. In total, 23 pts were evaluable with a median follow-up of 20.1 months (95%CI: 11.6-28.6). Median PFS, according to local site assessment, was 5.6 months (95%CI: 4.5-6.7); the 6m-PFSR was 10 of 23 pts (46%); (95%CI: 23-66) and median overall survival 10.3 months (95%CI: 6.7-13.9). In 19 pts with RECIST measurable response, 5 pts (26.3%) achieved a partial response; 10 (52.6%) stable disease and 4 (21.1%) PD. End-of-treatment reasons were PD in 21 pts (87%), toxicity 1 pt (4.2%) with two pts (8.4%) ongoing. For safety population, the most relevant study drug-related G3-4 toxicities were neutropenia (20.9%), anemia (16.7%), and increased ALT (12.5%). Conclusions: Sunitinib and nivolumab demonstrated encouraging activity in advanced DDCS that did not meet the primary endpoint, but compares favourably with previous analyses of cytotoxic and targeted therapy. The combination is worthy of further exploration in conjunction with reaching a consensus on clinically meaningful endpoints in this challenging population. Translational studies to identify potential predictive biomarkers are ongoing. Clinical trial information: NCT03277924 .

Community oncology preparedness and perceptions of challenges in care with HER2/HER3 therapy for NSCLC.

e21010 Background: The rapid pace of advances in molecular testing and targeted treatment for non-small cell lung cancer (NSCLC) can make it difficult to stay up to date with new developments. Accelerating the integration of practice-changing data requires clarification of actionable vs non-actionable mutations, relevance for therapeutic decisions, and treatment options for patients. To address this need further an educational program was designed in 2023. Methods: A one-hour online, video-based program was designed for clinicians and their teams and hosted on OMedLive from February 2023. Knowledge and competence questions were administered pre-, and immediate post-activity. and the intersection of patient and clinician perspectives, including behavioral impact, and qualitative insights. Behavioral impact, perception, and practice pattern questions were also assessed immediately post-activity. Results: More than 1,700 participants have engaged in the educational program to date. Of the participants in the clinician program, 94% were physicians and 93% noted their specialty as oncology with 67% identifying as treaters seeing an average of 8 patients with NSCLC on a monthly basis. Low baseline (8% - 40%) knowledge and competence was observed for awareness of NGS-based approaches to detect ERBB2 mutations, trial eligibility criteria and outcomes, time to onset of drug-related toxicities, and ability to identify patients who would benefit from clinical trials with HER3 investigational therapies. Only 28% were confident in their ability to appropriately test for HER2 mutational status and 47% likely to incorporate testing for HER2 expression level or amplification prior to the selection of targeted therapy. The greatest challenges in managing patients with HER2-mutated NSCLC was identified as managing side effects (33%), affordability of therapy for patients (27%), and adherence to treatment schedules (17%). Conclusions: The outcomes of this educational program demonstrate a need for greater alignment and education among pathology and oncology team members on HER2 testing for patients with NSCLC. Additional education is needed relevant to investigational HER3 therapeutics, the appropriate patient to receive these therapies, and the potential application within the current treatment landscape. As these agents deepen their impact in the NSCLC landscape, it is important to prepare teams for timely management of adverse events.

CD44 and its implication in neoplastic diseases.

CD44, a nonkinase single span transmembrane glycoprotein, is a major cell surface receptor for many other extracellular matrix components as well as classic markers of cancer stem cells and immune cells. Through alternative splicing of CD44 gene, CD44 is divided into two isoforms, the standard isoform of CD44 (CD44s) and the variant isoform of CD44 (CD44v). Different isoforms of CD44 participate in regulating various signaling pathways, modulating cancer proliferation, invasion, metastasis, and drug resistance, with its aberrant expression and dysregulation contributing to tumor initiation and progression. However, CD44s and CD44v play overlapping or contradictory roles in tumor initiation and progression, which is not fully understood. Herein, we discuss the present understanding of the functional and structural roles of CD44 in the pathogenic mechanism of multiple cancers. The regulation functions of CD44 in cancers-associated signaling pathways is summarized. Moreover, we provide an overview of the anticancer therapeutic strategies that targeting CD44 and preclinical and clinical trials evaluating the pharmacokinetics, efficacy, and drug-related toxicity about CD44-targeted therapies. This review provides up-to-date information about the roles of CD44 in neoplastic diseases, which may open new perspectives in the field of cancer treatment through targeting CD44.