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: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.

e23024 Background: Over the last decades, there has been a surge in the development and approval of targeted drugs and immunotherapies for treating cancer patients, as seen by the 757 % increase in approvals by the FDA for new cancer treatments since 2000 (1). This has significantly impacted cancer care and contributed to improving overall survival in various cancer subgroups. However, access to these new treatments is constrained by the market access strategy of the patent-owning company and available knowledge of treatment effects. Only a few treatments have received pan-cancer approval from EMA or FDA, and most drugs receive market authorization per indication. As a result, there is a widening access gap between patients with different cancer types (2). Methods: Exploring the effect of biomarker-driven treatments in new cancer subtypes requires the ability to find patients with rare biomarkers. PRIME-ROSE is a European precision medicine network comprising 11 ongoing or soon-to-start national DRUP-like clinical trials testing registered drugs outside their current label ( www.prime-rose.eu ). Patients with relevant tumor biomarkers are identified and treated with matched drugs available in each trial’s drug portfolio. The ambition is to swiftly and systematically evaluate the effectiveness of approved precision cancer medicines in new indications through pragmatic trial designs and with RWE control cohorts, ensuring expansion into all relevant patient groups to maximize societal benefit. This is particularly relevant for rare cancers, which are enriched in precision medicine trials (3). Results: In PRIME-ROSE, the trials now share and aggregate data to build evidence faster and more effectively impact patient care by addressing key challenges in precision cancer medicine implementation (increasing the recruitment area to 71 million inhabitants). This will significantly reduce the time for filling treatment cohorts and contribute to closing the indication/drug-specific knowledge gap. In fact, several pharmaceutical companies have already shown their interest in and commitment to participating in PRIME-ROSE, as it offers the unique advantage of entering the trials in the network simultaneously (single point of entry) and with a floating allocation of treatment slots between trials, increasing efficiency in finding patients with specific biomarkers to fill treatment cohorts. Conclusions: A unified entry point to the PRIME-ROSE network is feasible and can facilitate building the knowledge base faster for label expansion and/or country-specific approvals/ reimbursement. National multi-stakeholder ecosystems that include pragmatic, RWE-controlled DRUP-like clinical trials may advance precision medicine implementation. References: 1) Scott EC et al. Nat Rev Drug Discov, 2023, 22:625-640. 2) André F et al. Nature, 2024, 626:26-29. 3) Hoes LR et al. Clin Cancer Res, 2022 28:1402-1411.

2641 Background: BI-1808 is an IgG1 mAb that target TNFR2 by blocking interaction of TNFR2 with ligand TNF-α, confers FcγR-dependent depletion of Treg and mediates expansion of intratumoral CD8+ T cells. Upon co-administration of murine surrogate antibodies targeting TNFR2 and anti-PD-1 to immunocompetent tumor-bearing mice with partial sensitivity to checkpoint blockade, complete cures were observed in all treated mice. Thus, targeting TNFR2 by this approach offers a promising and novel treatment of cancer paradigm for patients. Methods: Safety and tolerability profile of BI-1808 as a single agent and in combination with pembrolizumab is currently being investigated in the Phase 1/2a clinical trial 19-BI-1808-01, enrolling patients with advanced solid malignancies or T-cell lymphomas, including CTCL. The study consists of Phase 1 dose escalation of single agent and combination with pembrolizumab. Phase 2a consists of dose expansion as single agent and as combination therapy in separate cohorts for OC, NSCLC, TCL/CTCL and Melanoma. Response is assessed according to RECIST and iRECIST. Results: As of Jan 12, 2024, 31 subjects received doses of up to 1000 mg BI-1808 as single-agent Q3W and 13 subjects received BI-1808 at 225 mg or 675 mg in combination with pembrolizumab 200 mg Q3W. Across the completed monotherapy arm dose escalation covering 25 to 1000 mg dose, no Gr3/4 AEs related to BI-1808 monotherapy were observed. Number of potentially related AEs of Gr1/2 have been evenly distributed across the dose range, with no target organ class of notice identified. 5 Gr1/2 IRR were observed, and in the combination arm 1 DLT (colitis) was observed in the 225 mg cohort. Best clinical response recorded in monotherapy arm was 1 iPR out of 20 evaluable patients, and 6 patients showing SD. The iPR was observed in a metastatic GIST patient with 12 prior lines of treatment. After initial pseudo-progression, a robust and ongoing response has been observed in this patient with several target lesions non-detectable and 60% SLD reduction from baseline. In addition, one previously untreated NSCLC showed reduction in several target lesions at 3 months when treatment terminated for unrelated reasons. Interestingly, both patients showed clear signs of T-cell activation in blood and tumor, strongly suggesting that T-cell responses underlie the tumor regressions. In the combination cohort with pembrolizumab 1/4 patients showed SD at 225 mg. At doses of ≥ 675 mg Q3W, BI-1808 t½ was approximately one week leading to accumulation of drug, leading to complete receptor occupancy throughout the dosing interval, a substantial increase in sTNFR2 and a significant reduction of regulatory T-cells. Conclusions: Preliminary data from dose escalation phase is promising. BI-1808 has a favorable safety profile, with early signs of monotherapy activity, and is well tolerated when combined with pembrolizumab. Clinical trial information: NCT04752826 .

2593 Background: PD-1 blockade has demonstrated positive anti-tumor activity across multiple tumor types. While the anti-tumoral response can be substantial and even curative, response rates remain low in many cancer types. Long-lasting responses are only observed in a minority of patients, and additional immunotherapeutic alternatives remain limited for patients who fail to respond or initially respond but subsequently experience progression. Combining anti-PD-1 with other immunotherapies may improve the durability and depth of anti-tumoral immune responses. Non-clinical data suggest anti-PD-1 interactions with macrophage Fc gamma receptors (FcγRs) compromise therapeutic activity by several mechanisms including the rapid removal of anti-PD-1 from its target on CD8+ T-cells and phagocytosis of anti-PD-1 coated CD8+ T cells. Accordingly, we and others have shown that blockade of Fc/FcγR interactions with immunocompetent antibodies to the inhibitory FcγRIIB, a receptor highly upregulated in the tumor microenvironment, overcomes these resistance mechanisms and enhances anti-PD-1 efficacy in vitro and in vivo. BI-1206 is a fully human IgG1 targeting CD32b (FcγRIIB). Methods: This is a Ph1/2a trial in patients with advanced solid tumors who received previous lines of treatment with anti-PD 1/PD-L1 agents to evaluate safety, tolerability and PK/PD of BI-1206 at ascending IV and SC doses after coadministration with pembrolizumab Q3W using a mTPI-2 design. Results: Dose escalation with BI-1206 IV has been completed with no formal MTD defined. The most frequent related adverse events were infusion-related reactions, thrombocytopenia and elevated liver enzymes. All were transient without any clinical consequences, and adequate pre-medication with corticosteroids or split dose administration reduced the risk and/or intensity of these events. Out of 15 evaluable patients, 5 patients showed SD, including one lasting >24 months in a metastatic melanoma patient. Furthermore, long-lasting PR (>24 months) was observed in a uveal melanoma patient, and CR was observed in a metastatic melanoma patient who previously received three prior anti-PD-1 containing treatments (one including anti-CTLA4). Enrollment to BI-1206 SC dose escalation began Nov2023. Dose level and administration route to be further explored in Phase 2a will be determined after an integrated review of PK, PD and safety. The Ph2a consists of 3 expansion cohorts at the RP2D, each comprising a specific subset of subjects with advanced solid tumors (e.g., NSCLC, MM, and other tumors responsive to PD-1/PD-L1 inhibition). More than one dose level may be evaluated if warranted. Conclusions: Coadministration of BI-1206 with pembrolizumab was well tolerated in a heavily pretreated population, with promising hints of responses to be further explored in Ph2. Clinical trial information: NCT04219254 .

Background BI-1808 is a human IgG1 monoclonal antibody targeting TNFR2 by blocking the interaction of TNFR2 with its ligand TNF-α, confering FcγR-dependent depletion of intratumoral Tregs and mediating expansion of intratumoral CD8+ T cells. Upon co-administration of BI-1808 and anti-PD-1 surrogate antibodies to immunocompetent tumor-bearing mice, with partial sensitivity to checkpoint blockade, complete cures were observed in all treated mice, indicating a potentially synergistic activity. Methods Safety and tolerability of BI-1808 as a single agent and in combination with pembrolizumab is currently investigated in the Phase 1/2a trial 19-BI-1808–01 in patients with advanced malignancies or cutaneous T-cell lymphoma (CTCL). The trial consists of Phase 1 Parts A and B (dose escalation with single agent and combination with pembrolizumab, respectively), and Phase 2a Parts A and B (dose expansion with single agent and combination therapy, respectively). Dose escalation uses a modified toxicity probability interval-2 protocol (mTPI-2), investigating ascending dose levels of 25–1000 mg every three weeks (Q3W). Dose escalation aims to select both single agent RP2D and combination RP2D of BI-1808 for Phase 2a. Patients are sampled for pharmacokinetics (PK) of BI-1808, antidrug-antibodies and pharmacodynamics including lymphocyte subsets, regulatory T cells, memory T-cells, soluble TNFR2 serum concentration (sTNFR2) and BI-1808 receptor occupancy (RO). Results As of June 19th, 2023, 24 subjects with various advanced solid malignancies received doses of up to 1000 mg BI-1808 as single-agent treatment, and 7 subject received 225 mg doses of BI-1808 with pembrolizumab. Across the completed monotherapy arm, no Grade 3/4 AEs, AEs related to BI-1808 and no DLTs were observed. No MTD was defined. The number of potentially related AEs of Gr 1/2 are evenly distributed across the dose range, with no target system organ class of special notice identified. Best clinical response recorded are stable disease (SD) in 7/19 evaluable patients in the monotherapy arm. The first dose cohort for BI-1808 at 225 mg in combination with pembrolizumab is currently ongoing. BI-1808 exhibits a non-linear PK. At doses > 675 mg Q3W, t½ was approximately 1 week resulting in accumulation of drug, with complete RO throughout the dosing interval. Conclusions Preliminary data from the BI-1808 monotherapy arm from the clinical trial 19-BI-1808–01 is promising. BI-1808 has a favorable safety profile, with no DLTs observed. SD was observed in 7/19 evaluable patients. Doses of 675 mg and higher are expected to provide complete RO throughout the dose interval, and will be further explored in Ph2a.

Purpose: Although fatigue is a known side effect in patients with head and neck cancer (HNC) receiving radiation therapy, knowledge regarding long-term fatigue and dose-response relationships to organs at risk is scarce. The aim of this prospective study was to analyze patient-reported fatigue in patients with HNC receiving radiation therapy and to explore any possible association with organ-at-risk doses. Methods and Materials: Patients with HNC referred for curative radiation therapy were eligible for inclusion in the study. To assess patient-reported fatigue, quality of life questionnaires (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-FA12) were distributed before treatment and 1, 3, 6, 12, 24, and 60 months after the start of treatment. Mean dose (Dmean) and near maximum dose (D2%) of the cerebellum and brain stem were evaluated in relation to baseline-adjusted fatigue scores at 3 months. Results: One hundred twenty-six patients treated with intensity modulated radiation therapy between 2008 and 2010 were available for final analysis. Female sex and age <60 years were associated with higher fatigue at baseline, whereas patients also treated with chemotherapy had reduced physical and emotional fatigue at 6 months. Physical fatigue (QLQ-FA12 scale) increased from baseline up to 3 months (29 vs 59; P < .0001) but showed no difference compared with baseline from 1 to 5 years. Emotional fatigue was significantly lower at 5 years compared with baseline (14 vs 28; P < .0001). Patients with cerebellum Dmean > 3.5 Gy had higher mean physical fatigue scores at 3 months (38 vs 27; P = .036). Conclusions: Although there is a significant increase in fatigue scores for patients with HNC up to 1 year after radiation therapy, this study showed a return to baseline levels at 5 years. A possible association was found between physical fatigue and a higher mean dose to the cerebellum.

Precision radiation of immune checkpoint therapy resistant melanoma metastases (PROMMEL study): study protocol for a phase II open-label multicenter trial

Purpose: Knowledge of long-term health-related quality of life (HRQOL) in patients with advanced head and neck cancer treated with intensity modulated radiation therapy is scarce. Methods and Materials: HRQOL in 126 patients with advanced head and neck cancer treated with intensity modulated radiation therapy was followed longitudinally from diagnosis to 5 years after treatment with the European Organization for Research and Treatment of Cancer's QLQ-C30, the European Organization for Research and Treatment of Cancer's Head and Neck Cancer Module, and the M.D. Anderson Dysphagia Inventory. The survivors' HRQOL was compared with an age- and sex-matched normal population cohort. Results: At 5 years, 73 of the 95 surviving patients had completed the study. Significant reductions in general pain (29 vs 12), head and neck (HN) pain (22 vs 14), and feeling ill (20 vs 10) were found, and emotional functioning (70 vs 83) and global quality of life (67 vs 74) improved, compared with baseline values. Conversely, dry mouth (19 vs 56), senses (8 vs 27), teeth problems (10 vs 22), opening mouth (19 vs 56), and sticky saliva (15 vs 40) were markedly worse, although significant improvements had occurred over time after treatment. Anderson Dysphagia Inventory scores >80 at 5 years indicated good swallowing function. In a subgroup analysis, dry mouth and senses were significantly better in patients treated with chemoradiotherapy. Comparison to a normal population cohort's HRQOL shows that the study group experienced a wide array of symptoms affecting their quality of life. Conclusions: The results of this large, long-term follow-up study show that a majority of patients report a reasonable quality of life 5 years after treatment and that there seems to be continuous improvement over time. Comparison with a normal population cohort, however, underlines the fact that classical side effects remain, even with improved radiation techniques. Additional emphasis on normal-tissue-sparing radiation therapy is warranted, with close attention devoted to HRQOL outcomes. (C) 2019 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

PURPOSE:We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition).MATERIALS AND METHODS:Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects.RESULTS:Study inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P = .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray's test P = .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control.CONCLUSION:Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.

Abstract Objectives: Curative treatment of nasal cavity and paranasal sinus cancer is challenging due to the proximity to critical anatomical structures. The purpose of this study was to analyze the impact of trimodality therapy with preoperative chemotherapy and reduced-dose radiotherapy followed by organ-preserving surgery for treating patients with nasal cavity and paranasal sinus cancer. Methods: This retrospective study included all 156 patients diagnosed with sinonasal cancer in western Sweden between 1986 and 2009. We determined the treatment selection pattern and treatment outcomes for 79 patients treated with preoperative chemoradiotherapy. Results: Squamous cell carcinoma was the most common histology. The five-year overall survival was 54%, and 85% of these patients had T3 or T4 tumors. The five-year cumulative incidence rate of local recurrence was 32%. The five-year overall survival in patients with squamous cell carcinoma and adenocarcinoma was 45% and 76%, respectively. The median preoperative radiation dose was 48 Gy. Orbital exenteration was performed in 7% of patients. Conclusions: Preoperative chemoradiotherapy may be beneficial for patients with advanced sinonasal cancer when primary radical surgery is challenging. Survival outcomes were comparable to outcomes reported in the literature despite conservative surgery and relatively low radiation doses in patients with locally advanced tumors.

Objective: The purpose of this study was to prospectively and longitudinally compare the health-related quality of life (HRQOL) outcomes between head and neck (HN) cancer patients treated with parotid-sparing intensity modulated radiation therapy (IMRT) and patients treated with 3-dimensional conventional radiation therapy (3D-CRT). Methods and materials: Before and up to 12 months after treatment, HRQOL was recorded in patients with HN cancer who were referred to the Department of Oncology at Sahlgrenska University Hospital for curative IMRT. The study group's HRQOL was compared with a matched group of patients from previous descriptive HRQOL studies treated with 3D-CRT. Both groups' HRQOL was measured by the European Organization for Research and Treatment for Cancer QLQ-C30 and European Organization for Research and Treatment for Cancer QLQ-HN35 at 6 time points in the first year after diagnosis. Results: Two hundred and seven patients were included, 111 treated with IMRT and 96 matched controls treated with 3D-CRT. Both groups' HRQOL deteriorated during and after treatment. Just after treatment, worse HRQOL scores were observed in the IMRT group regarding insomnia (38 vs 27; P = .032), appetite loss (64 vs 50; P = .019), senses (54 vs 41; P = .017), and coughing (39 vs 26, P = .009). At 12 months, however, significantly better HRQOL scores were observed in the IMRT group regarding problems with dry mouth (72 vs 62; P = .018), pain (28 vs 20; P = .018), sexuality (37 vs 23; P = .016), social contacts (10 vs 6; P = .026), cognitive functioning (79 vs 87; P = .0057), and financial difficulties (12 vs 20; P = .0019). Conclusions: This study further supports the hypothesis that the introduction of IMRT has improved the long-term quality of life of HN cancer patients who have been treated with radiation therapy, but might cause more acute side effects. Longer follow-up is needed to study late complications.

Purpose: To examine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid beta-related processes could characterize the neurochemical response to cranial radiation.Methods and Materials: Before prophylactic cranial irradiation (PCI) of patients with small cell lung cancer, each patient underwent magnetic resonance imaging of the brain, lumbar puncture, and Mini-Mental State Examination of cognitive function. These examinations were repeated at approximately 3 and 12 months after radiation.Results: The major findings were as follows. (1) Cerebrospinal fluid markers for neuronal and neuroglial injury were elevated during the subacute phase after PCI. Neurofilament and T-tau increased 120% and 50%, respectively, after PCI (P<.05). The same was seen for the neuroglial markers YKL-40 and glial fibrillary acidic protein, which increased 144% and 106%, respectively, after PCI (P<.05). (2) The levels of secreted amyloid precursor protein-alpha and -beta were reduced 44% and 46%, respectively, 3 months after PCI, and the levels continued to decrease as long as 1 year after treatment (P<.05). (3) Mini-Mental State Examination did not reveal any cognitive decline, indicating that a more sensitive test should be used in future studies.Conclusion: In conclusion, we were able to detect radiation therapy-induced changes in several markers reflecting neuronal injury, inflammatory/astroglial activation, and altered amyloid precursor protein/amyloid beta metabolism, despite the low number of patients and quite moderate radiation doses (20-30 Gy). These changes are hypothesis generating and could potentially be used to assess the individual risk of developing long-term symptoms of chronic encephalopathy after PCI. This has to be evaluated in large studies with extended clinical follow-up and more detailed neurocognitive assessments. (C) 2014 Elsevier Inc.

Introduction Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs). Methods Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo. The primary endpoint was time to progression (TTP) of BMs. Results Fifty-four patients received enzastaurin and 53 patients received placebo. The median TTP of BMs was (months) enzastaurin: 6.9 (95% confidence interval [CI]: 3.4–11.9); placebo: 4.9 (95% CI: 3.6–not assessable); p = 0.82. Median overall survival (OS) was (months) enzastaurin: 3.8 (95% CI: 2.6–5.6); placebo: 5.1 (95% CI: 3.7–5.7); p = 0.47. Median progression-free survival (PFS) was (months) enzastaurin: 2.2 (95% CI: 1.1–2.3); placebo: 2.0 (95% CI: 1.3–2.3); p = 0.75. The overall response rate (ORR) for extracranial disease was enzastaurin: 0%; placebo: 4.5% (p = 0.49) and for intracranial disease was enzastaurin: 9.3%; placebo 6.8% (p = 0.71). Grade 4 hematologic treatment-emergent adverse events were (enzastaurin vs. placebo) thrombocytopenia (5.6% vs. 1.9%) and neutropenia (5.6% vs. 0%). There was 1 treatment-related death in each arm (enzastaurin: unknown cause; placebo: pulmonary embolism). No significant differences in health-related quality of life (HRQoL) were observed. Conclusions Enzastaurin was well tolerated but did not improve TTP of BMs, ORR, OS, PFS, or HRQoL after WBRT in LC patients with BMs.

Intestinal injury 4–48 hr after cytotoxic therapy (etoposide phosphate, 100 mg/kg body weight [bw], intravenously [i.v.]) was studied in rats using ligated intestinal loops. Chromium-51 ethylenediaminetetraacetic acid ( 51 Cr-EDTA) and rubidium-86 chloride ( 86 RbCl) were deposited intraluminally to determine the extent of the increase in intestinal permeability and ion channel disruption. Evans Blue (EB) was used for detection of endothelial leakage. Intestinal morphology was documented. Endothelial dysfunction, as observed by an increased extravasation of EB, was evident already 4 hr after cytotoxic therapy. Intestinal epithelial injury, as observed by an increase in 51 Cr-EDTA permeation and a decrease in 86 Rb absorption, occurred after 48 hr. Finally, histology disclosed a reduced crypt cell proliferation, displayed as a decrease in Ki67-positive cells. The findings suggest that, in the development of intestinal injury after cytotoxic therapy, endothelial disruption is an early event, whereafter epithelial dysfunction and crypt stem cell arrest occur. This knowledge could be of importance in the design of future intervention trials.