Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study.

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.

The innate immune landscape of dMMR/MSI cancers predicts outcome of nivolumab treatment: results from the Drug Rediscovery Protocol.

PURPOSE: Treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid dMMR/MSI tumors and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. PATIENTS AND METHODS: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol (DRUP), a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response (OR) or stable disease ≥ 16 weeks). Whole-genome sequencing and RNA-sequencing were performed on pre-treatment tumor biopsies. RESULTS: 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% (95% CI: 53 - 70) with an OR in 45% (95% CI: 36 - 54). After a median follow-up of 14.5 months (95% CI: 13 - 19), median progression-free survival was 18 months (95% CI 9 - not reached) and median overall survival was not reached. While CB was not or only weakly associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, where markers of adaptive immunity dominated the biomarker landscape. CONCLUSIONS: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor-type specific biomarkers for guiding immunotherapy.

The survival disparity between children and adolescents and young adults (AYAs) with Ewing sarcoma in the Netherlands did not change since the 1990s despite improved survival: A population-based study.

BACKGROUND: Adolescents and young adults (AYAs) with Ewing sarcoma have a worse prognosis than children. Population-based survival evaluations stratifying findings by important clinical factors are, however, limited. This Dutch population study comprehensively compared survival of children and AYAs with Ewing sarcoma over three decades considering diagnostic period, tissue of origin, tumor site, and disease stage. METHODS: Data on all children (0-17 years, N = 463) and AYAs (18-39 years, N = 379) diagnosed with Ewing sarcoma in the Netherlands between 1990-2018 were collected from the Netherlands Cancer Registry with follow-up until February 2023. Five-year relative survival was calculated using the cohort method. Multivariable analyses were conducted through Poisson regression. RESULTS: Children with Ewing sarcoma had a significantly higher 5-year relative survival than AYAs (65 % vs. 44 %). An increasing trend in survival was noted reaching 70 % in children and 53 % in AYAs in 2010-2018. Results were similar for Ewing bone sarcoma and extraosseous Ewing sarcoma. AYAs had a poorer prognosis than children for most tumor sites and regardless of disease stage. Survival probabilities were 60 % vs. 78 % for localized disease and 20 % vs. 33 % for metastatic disease. Multivariable-regression analysis, adjusted for follow-up time, diagnostic period, sex, disease stage, and tumor site, confirmed increased excess mortality among AYAs compared with children (excess HR: 1.7, 95 % CI: 1.3-2.1). CONCLUSIONS: Despite survival improvements since the 1990s, AYAs with Ewing sarcoma in the Netherlands continue to fare considerably worse than children. This survival disparity was present irrespective of tissue of origin, tumor site, and disease stage.

Impact of age on safety of Busulfan-Melphalan followed by autologous hematopoietic stem-cell transplantation versus standard chemotherapy in the patients of the EURO-E.W.I.N.G. 99 and Ewing 2008 clinical trials.

INTRODUCTION: Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. METHODS: We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. RESULTS: The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. CONCLUSION: The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.

The Variable Genomic Landscape During Osteosarcoma Progression: Insights From a Longitudinal WGS Analysis.

Osteosarcoma is a primary bone tumor that exhibits a complex genomic landscape characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence, and distant metastases. A comprehensive analysis of single-nucleotide variants (SNVs), structural variants, copy number alterations (CNAs), and chromothripsis events revealed the genomic heterogeneity during osteosarcoma progression. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during disease progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral, and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole-genome doubling in later occurrences. Large proportions of the genome were affected by loss of heterozygosity (LOH), although these regions remain stable during progression. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five of six osteosarcoma genomes are highly dynamic and variable during progression.

CSF1R Inhibition in Patients With Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase 1 Study of Vimseltinib.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

INTRODUCTION AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). CONCLUSION: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

Maximizing treatment opportunities: assessing protocol waivers' impact on safety and outcome in the Drug Rediscovery Protocol.

PURPOSE: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy. PATIENTS AND METHODS: DRUP is a multicenter, non-randomized clinical basket trial treating therapy-refractory cancer patients with molecularly targeted- and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and compared with outcomes of included patients that did not receive a waiver. RESULTS: Between September 1st 2016 and September 1st 2021, protocol waivers were granted for 82 patients (8%) out of 1019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria, other categories were out-of-window testing, treatment and testing exceptions. Serious adverse event rate was similar between patients that received a waiver (pW) and patients that did not (pNW): 39% vs. 41%, respectively (P=0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P=0.43). CONCLUSION: Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options.

Relative Wash-In Rate in Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a New Prognostic Biomarker for Event-Free Survival in 82 Patients with Osteosarcoma: A Multicenter Study.

BACKGROUND: The decreased perfusion of osteosarcoma in dynamic contrast-enhanced (DCE) MRI, reflecting a good histological response to neoadjuvant chemotherapy, has been described. PURPOSE: In this study, we aim to explore the potential of the relative wash-in rate as a prognostic factor for event-free survival (EFS). METHODS: Skeletal high-grade osteosarcoma patients, treated in two tertiary referral centers between 2005 and 2022, were retrospectively included. The relative wash-in rate (rWIR) was determined with DCE-MRI before, after, or during the second cycle of chemotherapy (pre-resection). A previously determined cut-off was used to categorize patients, where rWIR < 2.3 was considered poor and rWIR ≥ 2.3 a good radiological response. EFS was defined as the time from resection to the first event: local recurrence, new metastases, or tumor-related death. EFS was estimated using Kaplan-Meier's methodology. Multivariate Cox proportional hazard model was used to estimate the effect of histological response and rWIR on EFS, adjusted for traditional prognostic factors. RESULTS: Eighty-two patients (median age: 17 years; IQR: 14-28) were included. The median follow-up duration was 11.8 years (95% CI: 11.0-12.7). During follow-up, 33 events occurred. Poor histological response was not significantly associated with EFS (HR: 1.8; 95% CI: 0.9-3.8), whereas a poor radiological response was associated with a worse EFS (HR: 2.4; 95% CI: 1.1-5.0). In a subpopulation without initial metastases, the binary assessment of rWIR approached statistical significance (HR: 2.3; 95% CI: 1.0-5.2), whereas its continuous evaluation demonstrated a significant association between higher rWIR and improved EFS (HR: 0.7; 95% CI: 0.5-0.9), underlining the effect of response to chemotherapy. The 2- and 5-year EFS for patients with a rWIR ≥ 2.3 were 85% and 75% versus 55% and 50% for patients with a rWIR < 2.3. CONCLUSION: The predicted poor chemo response with MRI (rWIR < 2.3) is associated with shorter EFS even when adjusted for known clinical covariates and shows similar results to histological response evaluation. rWIR is a potential tool for future response-based individualized healthcare in osteosarcoma patients before surgical resection.

Testing dilemmas in the clinic: Lessons learned from biomarker-based drug development.

Various tests based on different biomarkers have been developed to identify the best candidates for poly(ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine.

Biological sample collection to advance research and treatment: a Fight Osteosarcoma Through European Research (FOSTER) and Euro Ewing Consortium (EEC) statement.

Osteosarcoma and Ewing sarcoma are bone tumours mostly diagnosed in children, adolescents and young adults. Despite multi-modal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been ground-breaking. Better understanding of biological subgroups, the role of the tumour immune microenvironment, factors that promote metastasis and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic and clinically linked biological analysis of patient samples but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage and analysis of patient samples. Two international panels of scientists, clinicians and patient and parent advocates have formed the Fight Osteosarcoma Through European Research (FOSTER) consortium and the Euro Ewing Consortium (EEC). The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, liquid biopsy tubes), handling and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonisation with practical, legal and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration and improve outcomes.

Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.

Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy.

In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (n = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (n = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland.

PCM4EU and PRIME-ROSE: Collaboration for implementation of precision cancer medicine in Europe.

BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.

Levels of circulating tumor DNA correlate with tumor volume in gastro-intestinal stromal tumors: an exploratory long-term follow-up study.

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.

The evolution of precision oncology: The ongoing impact of the Drug Rediscovery Protocol (DRUP).

BACKGROUND AND PURPOSE: The Drug Rediscovery Protocol (DRUP) is a Dutch, pan-cancer, nonrandomized clinical trial that aims to investigate the efficacy and safety of targeted and immunotherapies outside their registered indication in patients with advanced or metastatic cancer. PATIENTS: Patients with advanced or metastatic cancer are eligible when there are no standard of care treatment options left and the tumor possesses a molecular genomic variant for which commercially available anticancer treatment is accessible off-label in DRUP. Clinical benefit is the study's primary endpoint, characterized by a confirmed objective response or stable disease after at least 16 weeks of treatment. RESULTS: More than 2,500 patients have undergone evaluation, of which over 1,500 have started treatment in DRUP. The overall clinical benefit rate (CBR) remains 33%. The nivolumab cohort for patients with microsatellite instable metastatic tumors proved highly successful with a CBR of 63%, while palbociclib or ribociclib in patients with tumors harboring CDK4/6 pathway alterations showed limited efficacy, with a CBR of 15%. The formation of two European initiatives (PCM4EU and PRIME-ROSE) strives to accelerate implementation and enhance data collection to broaden equitable access to anticancer treatments and gather more evidence. CONCLUSION: DRUP persists in improving patients access to off-label targeted or immunotherapy in the Netherlands and beyond. The expansion of DRUP-like clinical trials across Europe provides countless opportunities for broadening the horizon of precision oncology.

Bevacizumab Treatment for Patients with NF2-Related Schwannomatosis: A Single Center Experience.

(1) Background: NF2-related schwannomatosis, characterized by the development of bilateral vestibular schwannomas, often necessitates varied treatment approaches. Bevacizumab, though widely utilized, demonstrates variable effectiveness on hearing and tumor growth. At the same time, (serious) adverse events have been frequently reported. (2) Methods: A single center retrospective study was conducted, on NF2-related schwannomatosis patients treated with bevacizumab from 2013 to 2023, with the aim to assess treatment-related and clinical outcomes. Outcomes of interest comprised hearing, radiologic response, symptoms, and adverse events. (3) Results: Seventeen patients received 7.5 mg/kg bevacizumab for 7.1 months. Following treatment, 40% of the patients experienced hearing improvement, 53%, stable hearing, and 7%, hearing loss. Vestibular schwannoma regression occurred in 31%, and 69% remained stable. Further symptomatic improvement was reported by 41%, stable symptoms by 47%, and worsened symptoms by 12%. Treatment discontinuation due to adverse events was observed in 29% of cases. Hypertension (82%) and fatigue (29%) were most frequently reported, with no occurrences of grade 4/5 toxicities. (4) Conclusion: Supporting previous studies, bevacizumab demonstrated positive effects on hearing, tumor control, and symptoms in NF2-related schwannomatosis, albeit with common adverse events. Therefore, careful consideration of an appropriate management strategy is warranted.

Efficacy of pembrolizumab and biomarker analysis in patients with WGS-based intermediate to high tumor mutational load: results from the Drug Rediscovery Protocol.

PURPOSE: To evaluate efficacy of pembrolizumab across multiple cancer types harboring different levels of Whole-Genome Sequencing (WGS)-based tumor mutational load (TML; total of non-synonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234). PATIENTS AND METHODS: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing. RESULTS: Seventy-two evaluable patients with 26 different histotypes were enrolled. CB rate was 13% in cohort A (3/24 with partial response (PR)), 21% in cohort B (3/24 with SD, 2/24 with PR), and 42% in cohort C (4/24 with SD, 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated. CONCLUSION: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study's primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.

Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands: data from a cross-sectional multicentre study.

PURPOSE: This study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life. METHODS: A cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30. RESULTS: In total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7-214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties. CONCLUSION: Even in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.

Factors Influencing the Outcome of Patients with Primary Ewing Sarcoma of the Sacrum.

Background: Ewing sarcoma (EwS) is a rare and highly malignant bone tumor primarily affecting children, adolescents, and young adults. The pelvis, trunk, and lower extremities are the most common sites, while EwS of the sacrum as a primary site is very rare, and only few studies focusing on this location are published. Due to the anatomical condition, local treatment is challenging in sacral malignancies. We analyzed factors that might influence the outcome of patients suffering from sacral EwS. Methods: We retrospectively analyzed data of the GPOH EURO-E.W.I.N.G 99 trial and the EWING 2008 trial, with a cohort of 124 patients with localized or metastatic sacral EwS. The study endpoints were overall survival (OS) and event-free survival (EFS). OS and EFS were calculated using the Kaplan-Meier method, and univariate comparisons were estimated using the log-rank test. Hazard ratios (HRs) with respective 95% confidence intervals (CIs) were estimated in a multivariable Cox regression model. Results: The presence of metastases (3y-EFS: 0.33 vs. 0.68; P < 0.001; HR = 3.4, 95% CI 1.7 to 6.6; 3y-OS: 0.48 vs. 0.85; P < 0.001; HR = 4.23, 95% CI 1.8 to 9.7), large tumor volume (≥200 ml) (3y-EFS: 0.36 vs. 0.69; P=0.02; HR = 2.1, 95% CI 1.1 to 4.0; 3y-OS: 0.42 vs. 0.73; P=0.04; HR = 2.1, 95% CI 1.03 to 4.5), and age ≥18 years (3y-EFS: 0.41 vs. 0.60; P=0.02; HR = 2.6, 95% CI 1.3 to 5.2; 3y-OS: 0.294 vs. 0.59; P=0.01; HR = 2.92, 95% CI 1.29 to 6.6) were revealed as adverse prognostic factors. Conclusion: Young age seems to positively influence patients` survival, especially in patients with primary metastatic disease. In this context, our results support other studies, stating that older age has a negative impact on survival. Tumor volume, metastases, and the type of local therapy modality have an impact on the outcome of sacral EwS. Level of evidence: Level 2. This trial is registered with NCT00020566 and NCT00987636.