Darolutamide suppresses the AR in NMRI nu/nu male mice effectively and safely. A-B: 16 NMRI nu/nu male mice subcutaneously bearing a PC346C tumor were treated for 14 days with 200 mg/kg darolutamide orally daily (n=4), 100 mg/kg darolutamide orally daily (n=4), were castrated and received vehicle (n=4) or were sham-castrated and received vehicle (n=4). Mean of prostate and seminal vesicle weight with SD is shown. *: p < 0.05; **: p < 0.01. C: Bodyweight of mice treated with darolutamide was not different from mice treated with vehicle, while bodyweight loss of castrated mice reached up to 5%, before recovery after 14 days.

INTRODUCTION:CDK4/6 inhibitors (CDK4/6i) improve progression-free survival in patients with advanced oestrogen-receptor-positive breast cancer. However, all CDK4/6i may increase creatinine levels, which can indicate kidney injury. In vitro research has shown that CDK4/6i can also inhibit tubular secretion of creatinine, thereby causing the phenomenon 'pseudo-acute kidney injury (pseudo-AKI)'. The incidence of pseudo-AKI is, however, unknown. We aimed to determine this incidence by assessing cystatin C, a protein filtered in the glomerulus without being subject to tubular secretion, in patients with creatinine increase during CDK4/6i treatment. METHODS:In this retrospective single-centre cohort study patients with breast cancer who received CDK4/6 inhibitors between January 1st 2017 and December 29th 2023 were screened for the incidence of creatinine increases suggesting potential kidney injury in the first six months of treatment. A significant creatinine increase was defined as 1) a creatinine plasma level of >90 µmol/L in women or >115 µmol/L in men and >10% increase from baseline creatinine plasma level or 2) a creatinine plasma level >1.5 times baseline creatinine or 3) an increase in creatinine plasma level from baseline with >26 µmol/L. Pseudo-AKI was diagnosed if the estimated glomerular filtration rate (eGFR) using cystatin C at the moment of creatinine increase was 1) equal or higher than eGFR using creatinine at baseline and/or 2) at least 25% higher than eGFR using creatinine at the moment of creatinine increase. The primary endpoint was the percentage of patients with pseudo-AKI analysed by means of the binomial probability test. RESULTS:Of the 234 patients treated with a CDK4/6i, 41 (17.5%) had creatinine levels indicating an AKI. From 22 of these 41 patients, cystatin C could be determined in retrospectively available serum. Pseudo-AKI was found in 16 out of 22 patients (73%, 95% CI 50-89%). In 5 out of 41 patients (12%) the CDK4/6i dose was unjustly adjusted or the drug was stopped due to creatinine increase. CONCLUSION:Pseudo-AKI has a high incidence in patients treated with CDK4/6i. Determining an eGFR based on the cystatin C value should therefore be considered as the first step when creatinine increases during CDK4/6i treatment.

Peritoneal metastases (PM), frequently observed in malignancies such as ovarian, colorectal, pancreatic, and gastric cancers, present a significant therapeutic challenge due to poor prognosis and limited effectiveness to systemic chemotherapy. The peritoneal–plasma barrier reduces effective drug transfer from plasma to the peritoneal cavity, reducing cytotoxic effects on PM. Intraperitoneal (IP) chemotherapy offers a locoregional approach, enabling high local drug concentrations that can enhance therapeutic efficacy while limiting systemic toxicity. The three major methods for IP administration—hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and catheter-based IP (CBIP) chemotherapy—each provide unique pharmacokinetic (PK) advantages for PM treatment. This review provides a comprehensive update on the pharmacological rationale of IP chemotherapy, focusing on drug characteristics that support extended IP retention and effective tumor targeting. The effects of administration variables are discussed, highlighting their role in optimizing IP drug exposure. Additionally, recent PK data on commonly used drugs in IP therapy, including platinum-based agents, taxanes, and novel nanoparticle formulations, will be evaluated. While PK rationale supports the administration of IP chemotherapy, further efficacy results from ongoing clinical trials are still awaited. Innovations in nanoparticle-based formulations and controlled-release systems offer substantial potential for improving both drug retention and targeted delivery, enhancing treatment precision and minimizing systemic toxicity. Continued exploration in these areas, along with optimization of IP administration protocols, is vital for advancing patient outcomes, refining therapeutic strategies, and maximizing the benefits of IP chemotherapy in clinical practice.

Background The peritoneum is a common metastatic site in gastric cancer. The prognosis of synchronous peritoneal metastases compared to other metastatic sites in gastric cancer remains understudied. This study aims to evaluate the impact of peritoneal metastases on survival in patients with metastatic gastric cancer. Methods Patients with gastric cancer and synchronous metastases between 2015 and 2020 were identified from the nationwide Netherlands Cancer Registry. Patients were categorized based on the site of metastases. Median overall survival (OS) was calculated for each metastatic site group. Multivariable Cox regression analyses were performed to evaluate the association between patient, tumour, and treatment characteristics, including the impact of systemic therapy, on OS. Findings A total of 4072 patients were included, of whom 1835 (45.1%) had peritoneal metastases. Of these, 58.1% had isolated peritoneal metastases. For patients with metastatic gastric cancer treated with systemic therapy, the median OS was 9.0 months (95% confidence interval (CI): 8.6-9.5), compared to 1.7 months (95% CI: 1.7-1.9) for treatment-na & iuml;ve patients, who received only palliative care. The survival for patients with isolated peritoneal metastases (4.4 months, 95% CI: 4.0-4.8 months) was similar to those with isolated non-peritoneal metastases (4.6 months, 95% CI: 4.2-5.1 months, adjusted HR: 0.94, 95% CI: 0.86-1.03, p = 0.185). Systemic therapy was associated with comparable survival in patients with peritoneal metastases and those with metastases at other sites. Interpretation This study demonstrates that there is no statistically significant difference in survival between patients with isolated peritoneal metastases and those with isolated non-peritoneal metastases in gastric cancer. Our findings emphasize the unique prognostic landscape for peritoneal metastases in gastric cancer, underscoring the need for disease-specific evaluations, rather than relying on assumptions derived from other cancer types.

BACKGROUND:Despite the implementation of DPYD genotype-guided dosing, approximately 1 in 3 patients receiving fluoropyrimidine-containing chemotherapy continues to experience severe toxicity. While clinical studies have demonstrated a favorable tolerance among highly selected fit older adults, real-world studies have shown an increased risk of toxicity. OBJECTIVE:To identify predictors of severe toxicity or treatment deintensification in older DPYD wild-type adults receiving fluoropyrimidine-containing chemotherapy. METHOD:Patients wild type for four tested DPYD variants, aged ≥65 years, who participated in a prospective clinical trial investigating genotype-guided individualized fluoropyrimidine dosing, were eligible for the study. The association between tumor-, treatment-, and patient-related characteristics and the occurrence of severe toxicity (grade ≥3, CTCAE v5.0) was analyzed in univariate and multivariate logistic regression analyses. The same analyses were performed for a composite endpoint of severe toxicity or treatment deintensification (including dose reduction, cycle delay, or discontinuation). RESULTS:A total of 311 patients were included. Median age was 71.2 years and 58.8% were male. Grade ≥3 toxicity occurred in 23.2% of patients. In multivariate analysis, none of the characteristics studied were significantly associated with the occurrence of grade ≥3 toxicity. The composite endpoint occurred in 41.2% of patients and was associated with the use of full dose monotherapy in multivariate analysis. CONCLUSION:Despite DPYD genotype-based dosing, grade ≥3 toxicity and treatment deintensification frequently occur in older patients treated with fluoropyrimidine chemotherapy. No patient-related variables were found to be associated with grade ≥3 toxicity, but treatment with dose-reduced monotherapy resulted in fewer treatment deintensification or severe toxicity events.

PURPOSE:The development of subcutaneous (SC) formulations for monoclonal antibodies (mAbs), as an alternative to conventional intravenous (IV) infusion, represents a shift in health care delivery. The relative environmental impact of these two administration methods is not well understood. Minimizing the environmental footprint of health care is crucial due to its substantial contribution to greenhouse gas (GHG) emissions. This study compared the carbon footprint of SC and IV administration using pertuzumab/trastuzumab as a case example. METHODS:A Life Cycle Assessment was conducted to compare the environmental impacts of IV versus SC administration of pertuzumab/trastuzumab, focusing on climate change impacts expressed in carbon dioxide-equivalents (CO2e). The analysis included emissions from single-use medical equipment, drug manufacturing, hospital operations, patient and staff transportation, and waste disposal. RESULTS:SC pertuzumab/trastuzumab resulted in slightly higher GHG emissions than IV administration, with 47.2 kg CO2e for loading doses compared with 45.9 kg CO2e, and 33.6 kg CO2e for maintenance doses compared with 32.9 kg CO2e. This increase was primarily due to the higher dosage required for SC delivery, with mAb production contributing the most to emissions. Nonetheless, SC administration reduced the use of single-use medical equipment and treatment-related energy consumption in health care facilities. Switching to SC pertuzumab/trastuzumab administration in the Netherlands in 2022 would have increased annual CO2e emissions by 12.2 tons, equivalent to driving 63,212 km in a petrol-powered car. CONCLUSION:Both IV and SC administration routes of mAbs have substantial environmental impacts, dominated by mAb production emissions. This research provides a framework for assessing the environmental impact of health care technologies and underscores the importance of integrating environmental considerations into health technology assessments to mitigate the significant contribution of health care to global GHG emissions.

11521 Background: Imatinib treatment for metastatic gastrointestinal stromal tumors (GISTs) has substantial overall survival benefits compared to chemotherapy (56 vs 9 months) (Balachandran, 2014). Even better outcomes have been demonstrated for patients with imatinib minimal drug concentrations (C min ) ≥ 1100 ng/mL (Demetri, 2009). Drug concentration-guided dosing through therapeutic drug monitoring (TDM) of imatinib has previously been described as an option for personalized dosing, but there is no definite conclusion on efficacy results (IJzerman, 2020). The aim of the current study was to evaluate the feasibility and effect on clinical outcomes of imatinib personalized dosing through TDM for GIST patients. Methods: GIST patients starting with imatinib 400 mg once daily (QD) in both the (neo)adjuvant and metastatic setting were included. C min levels were measured during routine outpatient clinic visits, at 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Dose increase to 600 mg QD and, if necessary, to 800 mg QD was advised when C min < 1100 ng/mL and treatment was well tolerated. Dose interventions were considered successful when median C min was ≥ 1100 ng/mL after intervention and no dose limiting toxicities (DLTs) occurred within the first month after dose intervention. Results: A total of 171 GIST patients were included, of which 61% (n = 104) were treated in the (neo)adjuvant setting and 39% (n = 67) in the palliative setting. Most patients (85.4%, n = 146) had a KIT exon 11 mutation. Median time on treatment was 30 months. A total of 1475 C min levels were measured (median of 8 levels per patient, IQR: 4−12), resulting in a median C min of 1111 ng/mL. Among all patients, 16% (n = 27) had all adequate C min levels, and 84% (n = 144) had ≥ 1 C min level below the target. Of these, 60% (n = 87) had a dose intervention, which was successful in 76% (n = 66) and unsuccessful in 24% (n = 21) of patients. When dose interventions were unsuccessful, this was primarily because C min levels were still below the target after the intervention (62%, n = 13). In the 40% of patients (n = 57) with ≥1 C min level below the target who had no dose intervention, this was mostly due to DLTs (51%, n = 29). Median C min before the dose intervention was 953 ng/mL, which increased to 1200 ng/mL (p < 0.001) after the intervention. DLTs were not correlated with dose interventions (p = 0.13; OR: 1.86, 95% CI: 0.83−4.16). Conclusions: This study confirms that personalized dosing of imatinib through TDM in GIST patients is feasible. Adequate drug concentrations improved from 16% to 54% of patients and interventions resulted in a clinically relevant drug concentration increase in patients who previously had C min levels below the target. Comparison of treatment efficacy and toxicity in our cohort with a standard-dose historical cohort will elucidate the effect of personalized dosing through TDM on clinical outcomes (analyses ready before ASCO). Clinical trial information: NTR6866 --- AND project number 11575 .

Cancer is increasingly prevalent among older adults with geriatric impairments, yet the impact of frailty on immune checkpoint inhibitor (ICI) therapy outcomes remains underexplored. This study aims to assess the association between frailty and grade ≥3 immune-related adverse events (irAEs), clinical benefit, all-cause hospitalization, and mortality in older patients undergoing ICI therapy. Patients aged ≥65 years, treated with anti-PD-1 monotherapy for a solid malignancy (September 2018-February 2024), were prospectively included in this multicenter study. The association between frailty, components of the geriatric assessment, and number of impaired geriatric domains with the occurrence of grade ≥3 irAEs, all-cause hospitalization, and clinical benefit was analyzed using univariable and multivariable logistic regression. Cox proportional hazards models were used to analyze all-cause mortality. Among the 110 patients, 55% were classified as frail. Grade ≥3 irAEs occurred in 17.3%, with no significant difference between frail and non-frail patients (18.0% vs. 16.4%, p = .814). Frailty was associated with higher hospitalization (OR: 3.98, 95%C.I.: 1.20-13.19) and mortality risk (HR: 5.23, 95%C.I.: 1.81-15.11). Multimorbidity (Charlson comorbidity index score ≥3) was also associated with hospitalization (OR: 5.54, 95%C.I.: 1.81-16.99). Frailty and the number of impaired geriatric domains were not associated with clinical benefit of ICIs in the palliative treatment setting (p = .374, and p = .155, respectively). Frailty should not be considered a contraindication for ICI therapy, as this therapy is generally well-tolerated, even among older frail patients. Instead, frailty should be viewed as a relevant clinical factor for optimizing therapeutic decision-making and tailoring supportive interventions in older patients.

Pemetrexed is a cornerstone in chemo(immunotherapy) of non‐small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra‐patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min). The pemetrexed dose was calculated based on renal function to reach a target AUC, and patients received oral folinic acid prophylaxis 45 mg four times daily on Days 2–15 of each cycle. Endpoints included safety (incidence of hematological and non‐hematological toxicity, treatment delays) and pharmacokinetics in line with regulatory guidance for renal impairment trials. Six patients with an estimated glomerular filtration rate (eGFR) between 26 and 41 mL/min were included. All patients were successfully escalated to the full dose. Adverse event patterns and pharmacokinetics were comparable to those in patients with normal renal function. Grade I/II anemia occurred in five patients (already present at baseline). One occurrence of grade IV neutropenia was observed, which resolved without intervention. Moreover, in three patients, a 1‐week treatment delay occurred. Treatment resulted in a response in four patients ( n = 1 complete response, n = 2 partial response, n = 1 stable disease). Pemetrexed can be safely administered in patients with impaired renal function when the dose is calculated based on renal function and folinic acid prophylaxis is administered, thereby enabling an effective treatment modality for patients that, thus far, could not be treated.

Background: Immune checkpoint inhibitors (ICIs) may increase the incidence of thromboembolisms (TEs). In patients with melanoma, the risk of TE and its association with the disease setting remains largely unknown. This study investigated the incidences of arterial thromboembolism (ATE) and venous thromboembolism (VTE) and associated risk factors in ICI-treated patients with melanoma in the advanced and adjuvant disease settings. Patients and methods: ATE and VTE incidences were retrospectively collected from patients receiving ICI in the advanced (irresectable stage III/IV) or adjuvant (stage III/IV, after complete resection) disease setting until 2 years or after censoring. Associations between characteristics and ATE/VTE were analyzed using the Fine–Gray model, with all-cause death as competing risk. Results: In the advanced disease cohort, 7 (2.2%) and 16 (5.1%) of 315 included patients developed ATE and VTE, respectively. In the adjuvant cohort, 3 (2.1%) and 2 (1.4%) of 143 included patients developed ATE and VTE, respectively. In the advanced cohort, ICI combination therapy was associated with VTE [standardized hazard ration (sHR) 4.42, 95% confidence interval (CI) 1.58-12.38, P = 0.005] and higher body mass index (BMI) with ATE (sHR 1.09 per point BMI increase, 95% CI 1.02-1.17, P = 0.017), with a trend toward VTE (sHR 1.06, 95% CI 1.00-1.13, P = 0.055). In the adjuvant cohort, VTE history was associated with increased combined TE (sHR 11.22, 95% CI 1.83-68.68, P = 0.009) and higher BMI with a trend toward increased TE (sHR 1.19, 95% CI 0.97-1.46, P = 0.091). Conclusions: Both ATE and VTE incidences seem to be modest in patients with melanoma receiving ICI in both disease settings. Patients with higher BMI and who are prescribed ICI combination therapy might be at increased thrombotic risk.

Background:Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of the anticancer drug olaparib, a CYP3A-substrate, has the potential to reduce PK variability, side effects and financial burden associated with this drug. After establishing adequate pharmacokinetic exposure with boosting in the PROACTIVE-A study, the PROACTIVE-B study is designed to evaluate non-inferiority for both efficacy and toxicity of the boosted therapy compared to the standard monotherapy of olaparib. Methods:The PROACTIVE-B study is a nationwide, multicentre, prospective, randomized, non-inferiority trial. A total of 142 patients (128 patients with BRCA+, high-grade, FIGO III/IV ovarian cancer who receive olaparib as maintenance therapy; 14 patients with other approved indications for olaparib) who start olaparib treatment in line with the drug label will be randomized between the standard monotherapy of olaparib 300 mg twice daily (BID) and the boosted therapy of olaparib 100 mg BID with cobicistat 150 mg BID. The co-primary objectives are tolerability (dose reductions due to toxicity), and efficacy (progression-free survival at 12 months) in the ovarian cancer population. Secondary objectives include health status (EQ-5D-5L), patient satisfaction (Cancer Therapy Satisfaction Questionnaire (CTSQ)), and cost effectiveness using the institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ) and iMTA Medical Consumption Questionnaire (iMCQ). Discussion:PK boosting of olaparib is a potentially valuable strategy to reduce the olaparib dose and the variability in olaparib exposure with fewer side effects. Moreover, the lower costs related to the boosted therapy contribute to a durable and accessible anticancer treatment for all patients. Trial registration:The PROACTIVE study has been published at ClinicalTrials.gov under NCT05078671 on October 14, 2021 and at EudraCT under 2021-004032-28 on August 24, 2021.

One dose does not fit all, especially in oncolytic drugs, where side effects and therapy failures highlight the need for personalized dosing approaches. In recent years, the quest to apply model-informed precision dosing to oncology drugs has gained significant momentum, reflecting its potential to revolutionize patient care by tailoring treatments to individual pharmacokinetic profiles. Despite this progress, model-informed precision dosing has not (yet) become widely integrated into routine clinical care. We aimed to explain model-informed precision dosing from a clinical viewpoint while addressing all prospective model-informed precision dosing implementation and validation studies in the field of oncology. We identified 16 different drugs for which prospective model-informed precision dosing validation/implementation has been performed. Although these studies are mostly focused on attaining adequate drug exposures and reducing inter-individual variability, improved clinical outcomes after performing model-informed precision dosing were shown for busulfan, and high-dose methotrexate. Toxicities were significantly reduced for busulfan and cyclophosphamide treatment. In contrast, for carboplatin, for which model-informed precision dosing has been used in the Calvert formula, no prospective validation on outcomes was deemed necessary as the therapeutic window had been extensively validated. Model-informed precision dosing has shown to be of added value in oncology and is expected to significantly change dosing regimens in the future.

BACKGROUND:Peritoneal metastases of gastric cancer are associated with a poor prognosis (median overall survival (OS) ∼9 months). Catheter-based intraperitoneal (CBIP) chemotherapy is a locoregional approach to deliver chemotherapy leading to higher intraperitoneal (IP) concentrations of cytotoxic drugs compared to intravenous administration. METHOD:This multicenter, open-label 3 + 3 + 3 dose-escalation phase I trial evaluated 3-weekly IP irinotecan with oral capecitabine and intravenous oxaliplatin (CAPOX). Patients with HER2-negative gastric cancer and macroscopic peritoneal metastases were included. IP irinotecan was administered on day 1 of a 3-weekly cycle. The primary objective was to establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary endpoints included safety, the pharmacokinetic profile of IP irinotecan, and clinical efficacy. RESULTS:A single DLT occurred in six patients in both the 50 mg and the 75 mg dose cohort. Two DLTs were observed in the three patients in the 100 mg dose cohort, estimating 75 mg IP irinotecan as the MTD. Treatment was well tolerated, with primarily low-grade adverse events, including gastrointestinal toxicity, bone marrow suppression, and peripheral neuropathy. The exposure to the active metabolite SN-38 was higher intraperitoneally than systemically (ratio of 2.1, range: range: 0.9-7.4). The median OS was 11.8 months (95 % CI: 5.5-18.0 months). CONCLUSION:Administration of 3-weekly CBIP irinotecan concomitant to systemic CAPOX was well tolerated at 75 mg in patients with gastric cancer and peritoneal metastases. Giving its promising clinical outcomes and the safety profile, CBIP of irinotecan provides a potential new treatment modality. A phase II study will commence to assess its feasibility and efficacy.

CPC634 is a core-crosslinked polymeric micelle entrapping docetaxel (DTX) developed to improve tolerability and tumour drug accumulation compared to conventional DTX. A pH-responsive covalent sulfone ester linker allows for controlled native DTX release. Prior research has shown CPC634's dose-proportional clinical pharmacokinetics (PK) and enhanced tumour uptake. Through population PK modelling, we aimed to predict the plasma PK and intratumoural PK of CPC634 and released DTX, focusing on how varying pH levels affect DTX release. Concentration-time data in blood and tumour from three clinical studies were used to build a population PK model. In vitro release of DTX from CPC634 was examined across pH values (5-7.4), measuring cumulative release over time to create pH-specific models. The clinical PK analysis showed that elimination of CPC634 was described by linear kinetics whereas release of DTX was found to be time-dependent. The in vitro DTX release rate in buffer and blood was described by first-order release (time-dependent) and (known) degradation processes. These findings were incorporated into the population PK model, allowing simulations to describe drug release behaviour. The in vitro findings indicated that DTX release rates of CPC634 increased with rising pH (positive correlation), as is expected from an ester linkage. The estimated clinical tumour DTX release rate from CPC634 was 1.23 * 10-3 h-1 corresponding with pH 5-6. Achieving a balance between nanoparticle stability in the circulation and efficient intratumoural release is critical for improving therapeutic efficacy. This underscores the importance of pH in the design of nanoparticles with temporarily covalently bound drugs.

Tamoxifen is an estrogen-receptor (ER) antagonist, used as adjuvant treatment of ER-positive breast cancer. It is converted by CYP2D6 into endoxifen, its most active metabolite. Patients with endoxifen plasma concentrations <16 nM face a higher risk of recurrence. The use of a priori model-informed precision dosing (MIPD) may lead to faster target attainment and thus potentially improve patient outcomes. In total, 106 evaluable patients were prospectively included in this single-arm MIPD-intervention study. Patients received a model-predicted tamoxifen dose when starting tamoxifen-treatment (65.1 % of patients received 20 mg, 16.0 % received 30 mg and 18.9 % received 40 mg). Seventy-five percent of the 40 mg group was predicted to be unable to reach the threshold of 16 nM despite receiving the highest registered dose. After attaining steady-state, 84.0 % of patients reached endoxifen levels >= 16 nM, which was not significantly higher compared to a historical control cohort (77.9 %, p = 0.17). The model showed adequate performance and correctly identified patients requiring 40 mg tamoxifen. Endoxifen samples that were acquired 4-6 weeks after treatment initiation, are informative of steady-state endoxifen levels and can be used to inform MIPD and adjust tamoxifen dosing prior to steady-state attainment. In this first MIPD implementation study for patients treated with tamoxifen, MIPD did lead to more patients achieving endoxifen levels >= 16 nM as compared to the one-dose-fits-all strategy, albeit insignificant. This may partly be explained by a larger proportion of patients who were recommended to switch to an aromatase inhibitor (AI) in the intervention cohort. In conclusion, MIPD seems beneficial compared to one-size-fits-all-dosing, but TDM still remains an important addition.

BACKGROUND:Data on exposure-response or exposure-toxicity relationships of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are limited and inconclusive. We aimed to investigate whether there is an association between palbociclib exposure and progression-free survival (PFS), adverse events (AEs) and dose reductions. MATERIALS AND METHODS:Data were retrieved from the prospective, multicentre SONIA trial in which patients with advanced estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer were randomised to receive CDK4/6i treatment in first versus second line. Blood for pharmacokinetics (PK) was taken at day 15 of cycles 1 and 2 during CDK4/6i treatment. Individual trough concentrations and plasma area under the curves of palbociclib were constructed using a population PK model. Associations with palbociclib exposure were tested using Cox regression for PFS and chi-square tests for AEs or dose reductions. RESULTS:PK data were available for 344 patients. No association between palbociclib exposure and PFS was found. Although patients with higher palbociclib exposure had more dose reductions during their entire CDK4/6i treatment course, this was not reflected by a higher incidence of grade 3-4 AEs in the first 3 months. CONCLUSION:The absence of an association between palbociclib exposure and PFS and the presence of the association between palbociclib exposure and dose reductions suggest that dose reductions may safely be carried out in case of palbociclib-related toxicity.

BACKGROUND:Immune checkpoint inhibitors (ICIs) improved survival in solid tumors but can cause immune-related adverse events (irAEs) that may affect quality of life (QOL) and physical functioning. The impact of severe irAEs on these outcomes remains unclear, particularly in frail older patients. This study evaluated the association between grade ≥ 3 irAEs and QOL and/or physical functioning over time in frail versus non-frail older patients receiving ICI therapy. METHODS:Patients aged ≥ 65 years with solid tumors treated with ICIs (September 2018-February 2024), were prospectively included in this multicenter study. QOL and physical functioning were evaluated at baseline, 6, and 12 months. Multivariable logistic regression models, adjusted for confounders, evaluated associations between severe irAEs and an unfavorable outcome (decline in QOL and/or physical functioning, or mortality). Secondary outcomes included the association of frailty and unfavorable outcomes, hospitalizations related to severe irAEs and treatment discontinuation due to irAEs. RESULTS:Among 169 patients (median age: 73 years, IQR: 71-78), 58 % were frail. Severe irAEs occurred in 22 % of patients at 6 months and 27 % at 12 months, with no differences by frailty status. Unfavorable outcomes occurred in 45.6 % at 6 months and 56.2 % at 12 months, with frail patients at higher risk at 6 months (OR: 2.14, 95 %C.I.: 1.01-4.52). Severe irAEs were not significantly associated with unfavorable outcomes at 6 or 12 months in the overall cohort or when stratified by frailty. Hospitalization rates were higher in frail patients (44 % vs. 19 %; p = 0.016), but not due to severe irAEs. CONCLUSION:Severe irAEs were not associated with unfavorable immunotherapy outcomes, regardless of frailty status. However, frailty was associated with unfavorable outcomes.

Table S3. Molecular Docking Positive