Abstract Background: Prior clinical strategies to target regulatory T cells (Tregs) have been limited by lack of tumor selectivity and efficacy. Chemokine receptor 8 (CCR8) is selectively enriched on intratumoral Tregs, providing a rationale to evaluate targeted Treg depletion in a first-in-human study using AMG 355, an afucosylated monoclonal antibody to CCR8. Methods: This multicenter, open-label, phase 1 study evaluated the safety, tolerability and preliminary antitumor activity of AMG 355 in adult patients (pts) with advanced solid tumors (non-small cell lung cancer, colorectal cancer, gastric cancer and melanoma) who had failed to respond or were intolerant to standard treatment. Participants were administered intravenous (IV) AMG355 given alone (Part 1A) or with 200 mg pembrolizumab Q3W (Part 1B). Both parts included dose escalation and backfilled cohorts with mandatory pre- and on-treatment tumor biopsies. The primary endpoints were safety, maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary endpoints were pharmacokinetics, preliminary antitumor activity, and pharmacodynamic effect on tumor CCR8+ cells on paired tumor biopsies. Results: As of December 7, 2025, 77 pts received AMG 355 alone (n=47) or in combination with pembrolizumab (n=30). Treatment-related adverse events (TRAEs) occurred in 74.5% and 80.0% of pts (including 4.3% and 16.7% grade ≥3 TRAEs) in Part 1A and Part 1B, respectively. Most common (%, all grades/grade ≥3) AEs were : infusion-related reactions (40.4/0) and pyrexia (21.3/0) in Part 1A; infusion-related reactions (36.7/0), ALT increase (23.3/3.3) and AST increase (23.3/0) in Part 1B. No dose-limiting toxicity was observed. MTD was not reached. Serum AMG 355 levels increased dose-proportionally in both monotherapy and pembrolizumab combination arms. Spanning multiple dose levels (70-700mg), the median %IPS (Immune cell Proportion Score: percentage of CCR8+ cells among immune cells measured by IHC) was 5 (range 0-25) prior to AMG 355 treatment (N=47). In pts whom paired biopsies were available with clinical activity (N=26), the baseline median CCR8 %IPS was 12.33 (range 2-20) in 7 pts with stable disease (SD) or partial response (PR), and 5 (range 0-25) in 19 pts with progressive disease (PD). For on-treatment (cycle 2) biopsies, the median CCR8 %IPS was 1 (range 0-5) in pts with SD/PR and 1 (range 0-6) in pts with PD. Objective responses were limited to two partial responses (one with melanoma in Part 1A and one with gastric cancer in Part 1B). SD was the best response in 9 pts (19.1%) in Part 1A and 10 pts (33.3%) in Part 1B. Conclusions: AMG 355 was safe and tolerable at doses up to 700 mg, but clinical activity as a single agent or combined with pembrolizumab was limited. Pharmacodynamic activity was observed, and further examination of the immune contexture is underway using digital pathology approaches. Citation Format: Antoine Hollebecque, Pilar Garrido Lopez, Marwan Fakih, Yasutoshi Kuboki, Markus Joerger, Jeong Eun Kim, Iwona Lugowska, Ivan Manuel Victoria Ruiz, Chia-Chi Lin, Fredericus Eskens, Ingrid Desar, Ming-Huang Chen, Caio Max Rocha Lima, Antoine Italiano, Haeseong Park, Abdulazeez Salawu, Kyriakos Papadopulos, Timothy Price, Tae Min Kim, Martina Imbimbo, Irene Vuu, Jackie Zhang, Theresa Alexander, Kumiko Isse, Elizabeth Finger, Olivier Mir, Oriol Mirallas. Initial results of a phase 1 study of AMG 355, a novel anti-CCR8 antibody as a single agent and in combination with pembrolizumab in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT003.

Score chart with predicted probability (%) to remain on WW at 12 months This model was based on the number of IMDC Risk factors (0, 1, 2), the number or involved organ sites (0 - 4) and the geometric mean [¹⁸F]FDG SUVmax as a continuous variable. The underlying formula is 100*(exp(-0.531)^exp(0.198*[IMDC score] + 0.039*[No of affected organ sites] + 0.170*[geometric mean [¹⁸F]FDG SUVmax] - 1.09))

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 .

Flow-chart patients according to RECIST-defined PD. *All patients had clinical disease progression; no CT-imaging was performed before initiation of systemic treatment ** In total 7 patients choose best supportive care. Three other patients underwent radiotherapy or surgery of all target lesions.

The HOLISTIC study assessed health-related quality of life (HRQoL) in advanced soft tissue sarcoma (STS) patients receiving first-line palliative chemotherapy. The secondary objective discussed here is to evaluate baseline self-reported financial difficulties and associated sociodemographic factors and global health status (GHS), compare financial toxicity between patients in the United Kingdom (UK) and the Netherlands (NL), and evaluate the consequences of financial toxicity. This prospective study included 72 UK and 65 NL patients. Financial toxicity was evaluated by the financial difficulties scale of the EORTC QLQ-C30. Associated factors (i.e., country, gender, educational level, relationship status, employment changes, income, age, time since diagnosis, and GHS) were analyzed using descriptive analysis, Chi-square tests, and univariate and multivariate logistic regression. Median participant age was 62 (range: 27–79) years, and gender distribution was equal. 58

PURPOSE:After initial approval of lenvatinib for radioiodine-refractory differentiated thyroid cancer (DTC), it has also shown promising outcomes in among others metastatic renal cell carcinoma (mRCC). Given that trial populations typically do not represent routine clinical care populations, questions arise about how applicable trial outcomes are in clinical practice. This study aims to compare the pharmacokinetics (PK), toxicity patterns, and survival data of lenvatinib in a real-world cohort with DTC and mRCC to those observed in pivotal clinical trials. MATERIALS AND METHODS:Patients were included when diagnosed with DTC or mRCC, had received current or prior treatment with lenvatinib, and had at least one available lenvatinib plasma concentration measurement. A descriptive comparison was made between the baseline characteristics, PK data, toxicity and survival data in this real-world cohort and those described in the phase III trials. RESULTS:Overall, 29 patients with mRCC and 35 patients with DTC were included. For mRCC, median time to treatment discontinuation (mTTD) was shorter than observed in the phase III trial (7.5 versus 11.0 months) with fewer dose-limiting toxicities, likely because 66% of the patients started with a reduced dose. mRCC patients were more pretreated and had a worse performance status than trial participants. This was resembled in overall lower PK exposure in mRCC patients. For DTC, mTTD was longer in our cohort (17.1 versus 13.8 months), with similar toxicity patterns and PK exposure as in the phase III trial. CONCLUSIONS:Our data suggests that patient characteristics and outcomes in routine clinical care deviate from clinical trials and show the need for alternative treatment strategies to manage tolerability to lenvatinib.

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. 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. 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.

Background:Previous research suggests that health-related quality of life (HRQoL) in patients with advanced soft tissue sarcoma (STS) is often severely impacted, but data on longitudinal changes during chemotherapy are lacking. We aimed to address this knowledge gap. Methods:This prospective, observational cohort study (HOLISTIC) assessed HRQoL in patients with advanced STS during first-line palliative chemotherapy, focusing on Global Health Scores (GHS) change after 4 cycles (T4). Eligible patients were recruited from five centres in the Netherlands (n = 63) and two centres in the United Kingdom (UK, n = 72). Clinical and sociodemographic data were collected, and HRQoL was measured using the EORTC QLQ-C30 at baseline (T0) and before each cycle. The primary outcome of this study was the change in GHS on the EORTC QLQ-C30 between baseline and after 4 cycles of first-line palliative chemotherapy. Changes in GHS were tested using paired sample t-tests and linear mixed-effects models (LME). For patients who did not complete 4 cycles, the last score post baseline (i.e. T3, T2) was used (i.e. T4/final). This study is registered with ClinicalTrials.gov, NCT03621332. Findings:Between March 2018 and March 2020, 137 patients from the UK (n = 72) and the Netherlands (n = 65) were enrolled. Two patients never started chemotherapy and were excluded. Of the remaining 135 patients, 60 (44%) had at least 4 cycles of chemotherapy and 91 (68%) completed the questionnaire at T0 together with at least the questionnaire at T2, T3 and/or T4. Mean GHS significantly deteriorated from 68.2 (T0) to 60.7 (T4/final) with a mean difference between T0 and T4/final of -11.3 points (95% CI 7.6-15.0, p < 0.001). GHS worsened both in patients with partial response/stable disease (-12.3 points, 95% CI 7.9-16.8, p < 0.001) and in patients with progressive disease (-10.9 points, 95% CI 2.3-19.6, p = 0.015). Baseline GHS were lower (i.e. worse) for patients with ECOG PS 1-2 (77.1 vs 84.7 [ECOG PS 0], p = 0.023), patients from the UK (77.4 vs 84.7 [NL], p = 0.008) and patients with anaemia (78.6 vs 84.7 [no anaemia], p = 0.040). The decline in GHS over time was more pronounced in patients with ECOG PS 0 (-4.7 points per cycle) compared to those with ECOG PS 1 or 2 (-1.4 points per cycle, (p = 0.014). Interpretation:First-line palliative chemotherapy in advanced STS is associated with a significant decrease in GHS, irrespective of tumour response. These results emphasise the importance of integrating patient-reported outcomes (PROs) in clinical trials and routine care, and may enable informed decision making by patients with advanced STS starting palliative chemotherapy. Future research should explore implementing PROs in practice, using them to guide treatment, and how chemotherapy vs disease progression affects QoL. Funding:Eli Lilly and Company.

Purpose: Moderate hypofractionation was adopted to reduce hospital visits during the COVID-19 pandemic aiming to maintain treatment efficacy for soft tissue sarcoma (STS) patients, shifting preoperative schedules from 25 fractions of 2 Gy to 14-15 fractions of 3 Gy. This study evaluates the clinical implications and outcomes of this schedule, focusing on wound complications, radiation toxicity, local tumour control, and distant metastases. Patients and Methods: Data was collected from patients treated between 01 and 01-2020 and 31-12-2023. Outcomes included wound complications within 120 days post-surgery, local-recurrence, distant metastases and radiation toxicity. Logistic regression was performed to identify factors associated with wound complications. The cumulative incidence of local recurrence and distant metastases were estimated with a competing risk model. Results: Sixty-six patients were analysed, with a mean age of 74 years (standard deviation (SD)+/- 11). Tumours were mainly localized in the lower extremities (64 %), mean size 103 mm (SD +/- 58). Median follow-up was 29 months (range 2-50). A R0 resection margin was achieved in 77% of the operated patients. The wound complication rate was 33%, with moderate complications in 13 patients and severe in 6. The cumulative incidences of local recurrence and distant metastases at 2 years were 7.6% (standard error (SE) 3.7%) and 29% (SE 6 %, Fig. 1) respectively. Acute grade 3 dermatitis occurred in one patient (1.5 %)and two patients experienced late grade 3 toxicity (fractures, 3.0 %). Twenty patients developed distant metastases, two diagnosed before start of the treatment. Eighteen patients died, with six deaths from distant metastases and one from the primary tumour. Conclusion: Preoperative moderate hypofractionation for STS during COVID-19 showed promising results, with no increase in postoperative wound complications and favourable local failure rates.

Background: Neoadjuvant imatinib therapy plays a crucial role in the management of gastrointestinal stromal tumors (GISTs), but its impact across various mutational profiles remains uncertain. Objective: The aim of this study is to describe the clinicopathological features and to assess the response and surgical outcomes of neoadjuvant imatinib in GIST patients exhibiting diverse mutational profiles. Methods: We conducted a retrospective study, extracting data from the Dutch GIST Registry, including patients treated with neoadjuvant imatinib. Response rate was the primary outcome, and secondary outcomes were the time on neoadjuvant treatment and resection margins (R0 vs. R1/R2), respectively. Results: Between 2009 and 2021, 326 patients were treated with neoadjuvant imatinib, of which 264 (80.9%) underwent resection. A total of 197 (74.6%) of them had a KIT-exon 11 mutation, 19 (7.3%) had other KIT mutations, 10 (3.8%) had PDGFRA D842 mutations, 21 (6.8%) had other PDGFRA mutations, 2 (0.7%) had NTRK mutation, 1 (0.4%) had an SDH mutation, and 17 (6.4%) had WT GISTs. Patients with KIT-exon 11 mutations demonstrated a higher rate of partial response to imatinib (60.5% vs. 33.3%; p = 0.00). A positive resection margin (R1 or R2) was observed in 14 (21.2%) patients with a non-KIT exon 11 mutations and in 11 (5.5%) patients with a KIT-exon 11 mutation (p = 0.00). Moreover, non-KIT exon 11 mutation patients had a shorter median duration of neoadjuvant therapy (5.3 months, range 0.5–21.0) compared to patients with a KIT exon 11 mutation (8.8 months, range 0.2–31.3; p < 0.001). Conclusions: Our study highlights the variability in treatment response associated with different GIST mutational profiles. Patients with a KIT-exon-11 mutation tended to respond more favorably to neoadjuvant imatinib in terms of partial response and surgical outcomes.

Flow diagram of patient enrolment. * Four patients were unfit for systemic treatment due to clinical deterioration resulting from rapid disease progression (n=3) or comorbidity and age (n=1). Three other patients did not wat systemic treatment.

Following patent expiration of branded imatinib (Glivec®), all Dutch patients with gastrointestinal stromal tumours (GIST) switched from Glivec to generic forms. Following this switch, many patients reported new symptoms. Therefore, we conducted this observational study to assess safety of generic imatinib among patients with GIST in the Netherlands. We included patients with GIST from four hospitals that switched from Glivec to generic imatinib. Within these patients, adverse events (AEs) without the switch to a generic were compared with AEs after the switch using a self-controlled case series design. The reference group was formed by the subset of patients who used imatinib for at least 1 year prior to the switch. As potential causes of increased AEs, we reviewed excipients and analysed plasma trough levels from 1 year prior to 1 year after the switch. In total, 201 patients switched to three generics: Accord® (n = 107), Amarox® (n = 81), and Sandoz® (n = 13). In the reference group (n = 150), 21.3

BACKGROUND:This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. PATIENTS AND METHODS:This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. RESULTS:This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. CONCLUSION:A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

Abstract Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison. Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials. TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ] Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT064.

Background: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposureeresponse e response relationship at the standard dose, and minimum target levels of drug exposure have been defined fi ned above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations >= 37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy fi cacy and toxicity. Patients and methods: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose- limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDMguided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing. Results: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002). Conclusions: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.

BACKGROUND:Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS:We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS:For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS:Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

BACKGROUND:In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. AIM:To determine attitudes and barriers to the implementation of TDM among Australian oncologists. METHODS:A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. RESULTS:Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. CONCLUSION:Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.

Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54

Patients with gastro-intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements. Between 2014 and 2021, six patients with KIT proto-oncogene, receptor tyrosine kinase (KIT) exon-11-mutated GIST from whom long-term plasma samples were collected prospectively were included in the study. ctDNA levels of relevant plasma samples were determined using the KIT exon 11 digital droplet PCR drop-off assay. Tumor volume measurements were performed using a semi-automated approach. In total, 94 of 130 clinically relevant ctDNA samples were analyzed. Upon successful treatment response, ctDNA became undetectable in all patients. At progressive disease, ctDNA was detectable in five out of six patients. Higher levels of ctDNA correlated with larger tumor volumes. Undetectable ctDNA at the time of progressive disease on imaging was consistent with lower tumor volumes compared to those with detectable ctDNA. In summary, ctDNA levels seem to correlate with total tumor volume at the time of progressive disease. Our exploratory study shows promise for including ctDNA testing in treatment follow-up.