Background and purpose The use of Magnetic Resonance imaging (MRI) for radiotherapy (RT) planning for locally advanced non-small cell lung cancer (LA NSCLC) could improve RT precision due to its superior soft tissue definition compared to computed tomography (CT). However, thoracic oncologists have limited experience of identifying thoracic structures on MRI. The aim of this study was to provide recommendations for MR sequences for thoracic organ at risk (OAR) contouring and present an atlas and descriptive instructions for delineation of thoracic OARs in the setting of MRI-guided radiation treatment planning and guidance. Materials and methods MRI scans were acquired in nine patients with early-stage lung cancer on a diagnostic 1.5 Tesla system. MRI sequences included T1-weighted and T2-weighted imaging techniques, each optimised for visualisation of particular OARs. OAR delineations were carried out and reviewed by an international panel of thoracic oncologists and MR radiologists. Results Thoracic MRI OAR contouring recommendations and atlas were developed by multi-institutional collaboration of six radiation oncologists and two MR radiologists. The atlas and contouring recommendations are described alongside high-resolution contoured MR images. Conclusions This consensus MRI contouring atlas has a variety of potential applications, from integration of MRI within the standard CT-based workflow in order to improve the contouring accuracy of challenging structures such as the brachial plexus, to forming the foundation of an MRI-only workflow for use in MRI-guided treatment machines. This guideline should provide a useful reference for education and will facilitate uniformity in MRI-based contouring of OARs.

Background and purpose The use of Magnetic Resonance imaging (MRI) for radiotherapy planning and guidance for locally advanced non-small cell lung cancer (LA NSCLC) is novel. The superior soft tissue definition of MRI compared to CT, may facilitate more accurate gross tumour volume (GTV) definition, with the goal of improving radiotherapy precision. This work aims to develop GTV contouring recommendations for NSCLC on MRI. Materials and methods Two international training workshops on GTV delineation for LA NSCLC were attended by thoracic radiation oncologists and MR radiologists. Thoracic radiation oncology experts contoured nine cases of LA NSCLC, firstly, on mid-position 4D-CT with PET-CT guidance, and secondly on non-contrast MRI, registered with the CT and PET-CT. Consensus contours generated on CT and MRI were discussed and finalised during two international meetings. Results Recommendations on GTV delineation for LA NSCLC for both the primary tumour and individual lymph node stations using thoracic MRI were produced and are provided in this document. Consensus contours generated on CT and MRI for specific clinical scenarios were demonstrated and challenges addressed. Conclusions We provide the first set of consensus recommendations on GTV contouring on MRI for LA NSCLC through an international collaborative process between international experts in thoracic radiation oncology and MR radiology. This work provides an initial step towards standardisation of lung GTV delineation on MRI which is necessary prior to any meaningful assessment of the benefits of MRI in GTV definition compared to current practice.

PURPOSE:The phase I Hybrid trial assessed the safety of combining simultaneous stereotactic body radiotherapy (SBRT) to the primary tumor and fractionated radiotherapy to the lymph nodes with concurrent cisplatin. MATERIALS AND METHODS:15 patients with stage III non-small cell lung cancer (NSCLC) with a peripheral primary tumor <5 cm were prospectively included and treated with concurrent daily low-dose chemoradiation using a hybrid fractionation schedule of simultaneous 24 fractions conventionally fractionated radiotherapy and 3 fractions SBRT. The allowed mean lung dose (MLD) was escalated by adapting the SBRT fraction dose between 14 and 18 Gy per fraction using the time-to-event continual reassessment method (TITE-CRM). RESULTS:All patients were able to be planned and treated per protocol. No dose-limiting toxicity was observed with a maximum treated MLD of 19.1 Gy. The most common Grade 1-2 toxicities consisted of radiation pneumonitis (N = 7) or rib fractures (N = 6). No G3+ pulmonary or mediastinal toxicities were observed. Although local and regional control were excellent (both 93%), 11 patients (73%) eventually developed progressive disease at distant sites at a median of 11 months. CONCLUSION:Simultaneous SBRT to the primary tumor and fractionated radiotherapy to the lymph nodes is feasible and safe with concurrent daily dose cisplatin with high loco-regional control rates.

The Response Evaluation Criteria in Solid Tumors (RECIST) have been the standard for assessing tumor response in oncology trials since 2000. Despite the use of these criteria, interobserver variability (IOV) remains a significant concern, as it can affect patient management and clinical trial outcomes. We aimed to review the current literature on factors contributing to IOV in RECIST. We conducted a systematic review to summarize potential factors that can contribute to variability, variance, or reproducibility in RECIST assessments: (I) manual measurements, (II) selection of lesions, (III) 1D diameters, (IV) intra-radiologist variability, (V) the experience of the readers, (VI) local vs centralized assessment, (VII) variations of criteria used, (VIII) type of imaging, (IX) follow-up schedule. Inclusion criteria required studies to use RECIST (1.0, 1.1, or modified versions), involve multiple response evaluations and provide comparative data on the same test subjects. We identified 246 studies, of which 88 met our inclusion criteria. Median sample size across studies was 50 patients (IQR: 25.8–90.8). Most studies (68.2

Introduction: Anti-PD1 in metastatic triple negative breast cancer (mTNBC) results in modest response rates but can lead to durable responses. Immunomodulatory strategies inducing a more inflamed tumor microenvironment (TME) could enhance response to anti-PD1. The TONIC1 trial explored immune induction strategies in relation to likelihood of response to PD1 blockade. Translational data of TONIC1 and the clinical data according to a pick-the-winner design identified low-dose doxorubicin and cisplatin as promising immune induction strategies [Voorwerk et al, Nat Med 2019]. Here, we present the randomized phase II TONIC2 study independently validating the benefit of using low-dose doxorubicin or cisplatin as induction therapy before the start of anti-PD1 (NCT04159818). Methods: The non-comparative, phase II TONIC2 trial, using Simon’s two-stage design, randomized patients with mTNBC to nivolumab (nivo) with either 2-week low-dose doxorubicin induction (15mg, weekly) or no induction. After completing recruitment of these cohorts, next cohorts randomized to nivo without induction or with 2-week cisplatin induction (40mg/m2, weekly). Primary endpoint was progression-free survival (PFS). Metastatic lesion biopsies were taken at baseline, after induction and on nivo for bulk RNA-Seq, single-cell RNA-Seq and tissue imaging (MIBI, 37 markers), to assess the induction effects on the TME. Results: Among 97 randomized patients, 92 were evaluable for efficacy analyses (n=22 received doxorubicin followed by nivo, n=35 cisplatin followed by nivo, n=35 started directly with nivo without induction). The ORR was 20% in the control arm, 9% in the arm with doxorubicin induction and 9% in the arm with cisplatin induction. Median PFS (iRECIST) was 5.29 weeks (5.00 - 18.71) for patients in the doxorubicin arm, 5.86 weeks (5.14 - 17.00) in the cisplatin arm and 8.71 weeks (5.57 – 12.57) in the control arm. Median OS was similar across arms. The immunomodulatory effects of induction treatments on the TME were studied among all patients included in cisplatin, doxorubicin or control arms in TONIC1 and 2 (doxorubicin n=39, cisplatin n=48, no induction n=47). The control arm for postinduction comparisons consisted of patients who had a 2-week waiting period instead of induction treatment in TONIC1. The immunosuppressive Myc pathway decreased upon nivo compared to baseline in the doxorubicin induction arm (FDR<0.25). Immune checkpoints TIGIT and 4-1BB increased upon nivo after doxorubicin induction. Upon doxorubicin induction, deltas in PD-L1 CD8+ T cells, GLUT1+ CD8 T cells and HLADR+ CD4+ T cells were higher than in the control arm based on tissue imaging using MIBI. In addition, the delta of granulocyte to cancer cell ratio was lower in the doxorubicin arm. Upon induction with cisplatin, we observed an increase in IFNα response (FDR<0.25). The differential gene expression profile of postinduction biopsies showed increased levels of immune checkpoint molecules, MHCI and MHCII, cytokines and T cell markers compared to baseline. Upon nivo after cisplatin induction, we observed an increase in IFNγ, inflammatory response pathways and IL6 signaling compared to baseline (FDR<0.25). Detailed translational analyses, including single-cell RNA-Seq, and outcomes in relation to PDL1 expression will be presented at the meeting. Conclusion: Although exploratory results in the TONIC1 trial suggested a more favorable response rate upon nivo after induction with low-dose doxorubicin or cisplatin, these immune inductions did not result in significantly higher ORR/longer PFS in the independent and larger TONIC2 trial. In-depth translational analyses revealed modest but some favorable changes in the TME after induction with doxorubicin and cisplatin that could be important for future trial design. Citation Format: Marleen Kok, Veerle Geurts, Olga Isaeva, Manon de Graaf, Sara Balduzzi, Leonie Voorwerk, Ferry Lalezari, Michiel de Maaker, Nina Abbott, Iris Nederlof, Noah Greenwald, Thomas van Brussel, Mi He, Elisa Champanhet, Maksim Chelushkin, Ingrid Mandjes, Martine Heuver-Mes, Koen van de Vijver, Inge Kemper, Roberto Salgado, Hugo Horlings, Ton Schumacher, Lodewyk Wessels, Diether Lambrechts, Michael Angelo, Marleen Kok. Phase II adaptive TONIC2 trial to dissect immunomodulatory capacity of doxorubicin or cisplatin induction followed by anti-PD1 in mTNBC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-30.

Introduction: In osimertinib-treated EGFR mutation (EGFRm)–positive NSCLC, resistance inevitably occurs. Early resistance mechanism (RM) detection by circulating tumor DNA (ctDNA) in plasma and consecutive targeted treatment may delay progressive disease (PD). In this multicenter prospective study, we evaluated the detection rate and time interval of RM emergence in plasma ctDNA before radiologic PD. Methods: Patients with EGFRm–positive NSCLC, treated with second- or third-line osimertinib, underwent computed tomography of the thorax and ctDNA analysis (Roche AVENIO expanded panel, research use only [Roche Sequencing Solutions, Roche, Basel, Switzerland]) at baseline and every 8 weeks for response evaluation and EGFRm and RM detection. If MET amplification preceded PD, crizotinib was to be added to osimertinib. Other RMs were monitored but not acted on. After PD, patients underwent a tumor biopsy. Results: Of the 21 evaluable patients, 18 had detectable ctDNA at baseline. In patients with undetectable ctDNA at baseline, ctDNA remained undetectable during treatment. In the 17 out of 18 (94%) patients with detectable ctDNA, PD occurred. In seven out of 21 patients (33%), the EGFRm variant allele frequency increase preceded radiologic PD with a median interval of 9 weeks (range 7–34). In seven out of 21 patients (33%), at least one RM was detected before PD, and the median interval was 14 weeks (range 7–34). Three had one or more RM in ctDNA at baseline. No MET amplification was observed, and treatment with crizotinib was not initiated in any patient. After PD, 16 biopsies were obtained. Five confirmed the RM detected in plasma, five biopsies revealed additional RMs, and six harbored no RM. Conclusions: In 33% of patients treated with second- or third-line osimertinib, RMs in plasma preceded PD by a median of 14 weeks, suggesting an opportunity for early treatment adjustment, potentially extending tyrosine kinase inhibitor treatment duration.

METHODS:In this review, the historical development of tumor response criteria is examined and an interview was conducted with one of the original researchers behind the original study. This study, published nearly five decades ago, assessed tumor size through palpation and measurements of simulated tumor masses ("balls under mattresses"). The methodology used in that early study as well as in subsequent research that has influenced modifications of the current response evaluation criteria was critically evaluated. RESULTS:The current tumor response criteria trace back to a 1976 study by Moertel and Hanley, which relied on palpation to measure tumor size. The key outcome, a 50% reduction in the product of the longest perpendicular diameters of the most measurable tumor mass, formed the basis for later criteria. The World Health Organization criteria adopted these thresholds for response and introduced a 25% increase as a cutoff for progression. Later, unidimensional measurements replaced two-dimensional ones, with adjusted thresholds accordingly. These criteria further inspired the development of specialized response criteria such as Choi, mRECIST, and PERCIST. CONCLUSION:By analyzing the evolution of RECIST, it is highlighted that these criteria are not fixed standards but rather the product of a series of pragmatic choices and compromises rooted in their historical context. With advances in technology, including artificial intelligence and volumetric imaging, it is timely to reassess the reliability of current criteria and explore new approaches to tumor response evaluation.

BACKGROUND:Pembrolizumab (anti-PD-1 antibody) plus lenvatinib (multityrosine kinase inhibitor) showed high clinical activity in PEMMELA cohort 1 in patients with pleural mesothelioma pre-treated with platinum-based chemotherapy. This study (cohort 2) aimed to investigate the clinical activity of this combination in patients with pleural mesothelioma who progressed after first-line nivolumab plus ipilimumab. METHODS:PEMMELA is a prospective, single-centre, single-arm, open-label, investigator-initiated phase 2 trial, done at the Netherlands Cancer Institute, Amsterdam, the Netherlands. Cohort 2 included patients aged 18 years and older with histologically confirmed pleural mesothelioma, an Eastern Cooperative Oncology Group performance status 0-1, and measurable disease according to the modified Response Evaluation Criteria in Solid Tumors for mesothelioma version 1.1, who progressed after treatment with nivolumab plus ipilimumab. Pembrolizumab (200 mg every 3 weeks intravenously) plus lenvatinib (20 mg orally daily) was administered for up to 2 years, or until disease progression, or unacceptable toxicity. The primary endpoint was objective response rate assessed by the local investigator. All patients who had received at least one cycle of pembrolizumab plus lenvatinib and had their disease evaluated were considered evaluable for the primary endpoint. All patients who received at least one cycle of the study treatment were included in the safety analysis set. Patients were not involved in study design. This study is registered with ClinicalTrials.gov (NCT04287829), and is complete. FINDINGS:Between Dec 14, 2022, and March 5, 2023, 24 patients were screened, of whom 20 were enrolled and received at least one cycle of pembrolizumab plus lenvatinib. Of these 20 patients, 17 patients (85%) were male and three (15%) were female. At data cutoff (Sept 1, 2024), with a median follow-up of 11·9 months (IQR 10·8-15·8), 12 (60%, 95% CI 36-81%) of 20 patients had an objective response. 14 (70%) of 20 patients developed grade 3 or 4 treatment-related adverse events, of which most common grade 3 events were hypertension (five patients [25%]) and fatigue including malaise (four patients [20%]). Ten treatment-related serious adverse events were observed in seven patients. Nine (45%) of 20 patients required at least one dose reduction and two (10%) discontinued treatment due to toxicity. There were no treatment related deaths. INTERPRETATION:This study met its primary endpoint, showing high clinical activity of pembrolizumab plus lenvatinib, but with substantial toxicity, in patients with pleural mesothelioma who had progressed after first-line nivolumab plus ipilimumab. This drug combination is promising for future studies in pleural mesothelioma. FUNDING:Merck Sharp and Dohme.

BACKGROUND:The aim of this study was to describe the impact of surgical resections on tumour-infiltrating lymphocyte (TIL) therapy, based on results from a randomized phase III trial comparing TIL therapy with standard ipilimumab in patients with metastatic melanoma (NCT02278887). METHODS:Surgical details of all operations performed in the trial were collected. Location, total number, and size of resected metastases were assessed in relation to successful TIL investigational medicinal product (IMP) manufacture and response to TIL therapy. RESULTS:A total of 93 operations were needed to treat 80 patients with TIL therapy. Surgical complications were detected in 17% of operations. These were mostly mild Clavien-Dindo grade I/II complications and one Clavien-Dindo grade IIIa complication. The size or number of resected lesions did not significantly impact the TIL-IMP manufacture failure or response rate. The failure rate of TIL-IMP manufacture from lymph node metastases was 2.8% (1 of 36), which was lower than from subcutaneous metastases (19.4% (6 of 31), P = 0.037) and other sites (15.0% (3 of 20), P = 0.038). Response rates per resected lesion type were 52.9% (18 of 34) for lymph nodes, 40.9% (9 of 22) for subcutaneous lesions, 58.8% (10 of 17) for other lesions, and 60.0% (3 of 5) for combinations of lesions, without statistically significant differences. CONCLUSION:Tumour resections for TIL-IMP manufacture lead to limited surgical complications. Manufacture with a therapeutic response was successful using lesions of varying sizes from different anatomical locations, with highest rates for lymph nodes.

Two decades after the genomics revolution, oncology is rapidly transforming into a genome-driven discipline, yet routine cancer diagnostics is still mainly microscopy based, except for tumor type-specific predictive molecular tests. Pathology laboratories struggle to quickly validate and adopt biomarkers identified by genomics studies of new targeted therapies. Consequently, clinical implementation of newly approved biomarkers suffers substantial delays, leading to unequal patient access to these therapies. Whole-genome sequencing (WGS) can successfully address these challenges by providing a stable molecular diagnostic platform that allows detection of a multitude of genomic alterations in a single cost-efficient assay and facilitating rapid implementation, as well as by the development of new genomic biomarkers. Recently, the Whole-genome sequencing Implementation in standard Diagnostics for Every cancer patient (WIDE) study demonstrated that WGS is a feasible and clinically valid technique in routine clinical practice with a turnaround time of 11 workdays. As a result, WGS was successfully implemented at the Netherlands Cancer Institute as part of routine diagnostics in January 2021. The success of implementing WGS has relied on adhering to a comprehensive protocol including recording patient information, sample collection, shipment and storage logistics, sequencing data interpretation and reporting, integration into clinical decision-making and data usage. This protocol describes the use of fresh-frozen samples that are necessary for WGS but can be challenging to implement in pathology laboratories accustomed to using formalin-fixed paraffin-embedded samples. In addition, the protocol outlines key considerations to guide uptake of WGS in routine clinical care in hospitals worldwide.

Background The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.Methods In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged >= 18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort.Findings Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17 center dot 7 months (IQR 13 center dot 8-19 center dot 4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required.Interpretation Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in mesothelioma.

This file contains details on loco-regional control, progression free survival and overall survival split by treatment arm.

Malignant pleural mesothelioma (MPM) is an aggressive primary malignancy of the pleura that presents unique radiologic challenges with regard to accurate and reproducible assessment of disease extent at staging and follow-up imaging. By optimizing and harmonizing technical approaches to imaging MPM, the best quality imaging can be achieved for individual patient care, clinical trials, and imaging research. This consensus statement represents agreement on harmonized, standard practices for routine multimodality imaging of MPM, including radiography, computed tomography, 18F-2-deoxy-D-glucose positron emission tomography, and magnetic resonance imaging, by an international panel of experts in the field of pleural imaging assembled by the International Mesothelioma Interest Group. In addition, modality-specific technical considerations and future directions are discussed. A bulleted summary of all technical recommendations is provided.

This file contains details on pulmonary function changes in diffusion tests (I) and spirometry tests (II), and the incidence of severe pulmonary adverse events by treatment arm (III).

This file contains details on DLT (I) and DLT probabilities according to TITE-CRM in the CCRT arm (II) and (SC)RT study arm (III).

BACKGROUND AND PURPOSE:We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer. MATERIALS AND METHODS:Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions. The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II 'pick-the-winner' design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year. CLINICALTRIALS:gov:NCT01024829. RESULTS:150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91-100) in whole tumour group, and 91 % (95 %CI 82-100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group. CONCLUSION:Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

This file contains details on all late grade {greater than or equal to} 2 esophageal adverse events (I) and esophageal metabolic activity six weeks post-treatment (II).