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Positron emission tomography (PET) with H2 [15]O and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide noninvasive measurements of tumor blood flow. Both tools offer the ability to monitor the direct target of antiangiogenic treatment, and their use is increasingly being studied in trials evaluating such drugs. Antiangiogenic therapy offers great potential and, to an increasing extent, benefit for oncological patients in a variety of palliative and curative settings. Because this type of targeted therapy frequently results in consolidation of the tumor mass instead of regression, monitoring treatment response with the standard volumetric approach (Response Evaluation Criteria in Solid Tumors) leads to underestimation of the response rate. Monitoring direct targets of anticancer therapy might be superior to indirect size changes. In addition, measures of tumor blood flow contribute to a better understanding of tumor biology. This review shows that DCE-MRI and H2 [15]O-PET provide reliable measures of tumor perfusion, provided that a certain level of standardization is applied. Heterogeneity in scan acquisition and data analysis complicates the interpretation of study results. Also, limitations inherent to both techniques must be considered when interpreting DCE-MRI and H2 [15]O-PET results. This review focuses on the technical and physiological aspects of both techniques and aims to provide the essential information necessary to critically evaluate the use of DCE-MRI and H2 [15]O-PET in an oncological [ABSTRACT FROM AUTHOR]

Background: Diagnosis and treatment of leptomeningeal metastases (LM) in epidermal growth factor receptor mutation-positive (EGFRm +) non-small-cell lung carcinoma (NSCLC) is challenging. We aimed to identify resistance mechanisms (RM) to osimertinib in cerebrospinal fluid (CSF) and plasma., Methods: EGFRm + patients with new or progressive LM during osimertinib were enrolled. NGS Ampliseq was performed on DNA isolated from CSF. Patients were prescribed osimertinib dose escalation (DE, 160 mg QD) following lumbar puncture. Clinical and radiological response was evaluated 4 weeks after osimertinib DE., Results: Twenty-eight patients were included. The driver mutation was identified in 93% of CSF samples (n = 26). Seven (27%) harbored ≥1 RM. Twenty-five patients (89%) were prescribed osimertinib DE. Four weeks afterwards, symptoms improved in 5 patients, stabilized in 9 and worsened in 11 patients. Twenty-one (84%) patients underwent MR imaging. Four showed radiological improvement, 14 stabilization, and 3 worsening., Conclusions: In 27% of patients, an RM was found in CSF ctDNA, none of which are targetable at the time of writing, and the clinical efficacy of osimertinib DE seems limited. There is much to gain in diagnostic as well as therapeutic strategies in EGFRm + NSCLC LM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse., Patients and Methods: In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies., Results: Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations., Conclusions: Crizotinib is a valuable treatment option in METmut aNSCLC., (©2024 American Association for Cancer Research.)

Introduction: Osimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib., Methods: From 09 - 2019 to 02 - 2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥0.10%. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice., Results: The driver mutation was detected in 42/51 plasma samples (82%) and in 50/51 tumor samples (98%), concordance rate was 80%. In 41/51 (80%) patients ≥1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5%), 39 in tumor (75%), nineteen in both. RM concordance rate was 36.5%., Conclusion: Combined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Baas reports a grant from BMS, unrestricted to the hospital, as well as consulting fees paid to the hospital by BMS, MSD, AMheart, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to the hospital from BMS. Burgers reports a grant from MSD as support for an investigator initiated study, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to the hospital from MSD, participation on a data safety monitoring board or advisory board with Roche, paid to the hospital, and receipt of free drugs for an investigator initiated study from MSD. Hashemi reports grants from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Janssen, GSK, MSD, Novartis, Roche and Takeda, all to the institution. De Langen reports grants from BMS, grants from MSD, grants from Boehringer, non-financial support from Merck Serono, grants from AstraZeneca, non-financial support from Roche, outside the submitted work. Monkhorst reports consulting fees from Lilly, Bayer and Amgen, all paid to the institution. Smit reports consulting fees from Eli Lilly, AstraZeneca, MSD, Merck, BMS, DSI, Takeda and Boehringer Ingelheim, all paid to the institution, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with DSI. Theelen reports grants from Sanofi/Regeneron and MSD to the institution. Boelens, Bosch, Buikhuisen, van den Broek, Jebbink, van der Noort, Steinbusch, Ruiter, Vermeulen, van der Wel declare no potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The structural effect of uncommon heterogenous in-frame deletion and/or insertion mutations within exon 20 (EGFRex20+) in relation to therapy response is poorly understood. This study aims to elucidate the structural alterations caused by EGFRex20+ mutations and correlate these changes with patient responses., Material and Method: We selected EGFRex20+ mutations from advanced NSCLC patients in the Position20 and AFACET studies for computational analysis. Homology models representing both inactive and active conformations of these mutations were generated using the Swiss-Model server. Molecular docking studies with EGFR-TKIs was conducted using smina, followed by Molecular Dynamic (MD) simulations performed with GROMACS. These computational findings were compared with clinical outcomes to evaluate their potential in predicting patient response., Results: Our docking studies of 29 EGFRex20+ mutations revealed that the binding energies of afatinib, osimertinib, zipalertinib, and sunvozertinib, compared to the wild type, do not significantly impact either TKI's efficacy. MD simulations for eight EGFRex20+ mutations (A763_Y764insFQEA, A767_V769dup, S768_D770dup, D770_N771insG, D770_P772dup, N771_H773dup, H773_V774insY and H773_V774delinsLM) revealed varying degrees of instability. For six variants, predicted activation based on the αC-helix stability and orientation, as well as TKI sensitivity, aligned well with clinical observations from the Position20 and AFACET studies. Two mutations (D770_N771insG and N771_H773dup) predicted as poor to moderate responders, showed minimal activation of the αC-helix region, warranting further investigation., Conclusion: In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses., Competing Interests: Declaration of competing interest JM and MG are employees of Protyon, a spin-out company of the UMCG to provide molecular modeling support for clinical decision-making. ES reports lectures for Bio-Rad, Seracare, Roche, Biocartis, Illumina, Lilly, Janssen Cilag (Johnson&Johnson), AstraZeneca and Agena Bioscience; he is consultant in advisory boards for MSD/Merck, GSK, AstraZeneca, Astellas Pharma, Sysmex, Roche, Novartis, Bayer, BMS, Lilly, Amgen, Illumina, Agena Bioscience, Janssen Cilag (Johnson&Johnson), Sinnovisionlab, Diaceutics, CC Diagnostics and Protyon; and received research grants from Biocartis, Invitae-ArcherDX, AstraZeneca, Agena Bio-science, BMS, Bio-Rad, Roche, Boehringer Ingelheim, CC Diagnostics, SNN/EFRO and Abbott (all paid to UMCG account); and travel reimbursements from Bio-Rad, Abbott, Illumina, Agena Bioscience, Roche, IQNPath and BioRAD. BV has personal fees from Bristol-Myers Squibb, Johnson & Johnson en Astra Zeneca; outside the submitted work. AL reports grants from AstraZeneca, BMS, MSD, Boehringer Ingelheim, and non-financial support from Merck Serono and Roche, all outside the submitted work. AW has grants and personal fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Takeda, Janssen Cilag, Lilly, Amgen, Merck; outside the submitted work and all institutional payments. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Context.—: Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-targeted therapy, has demonstrated durable anticancer activity in patients with advanced, metastatic HER2 (also known as ERBB2)-mutant (HER2m) non-small cell lung cancer (NSCLC) who have limited treatment options and poor prognosis., Objective.—: To analytically validate and assess the clinical utility of the Oncomine Dx Target (ODxT) Test as a companion diagnostic to identify patients with HER2m NSCLC., Design.—: Tumor samples from patients in DESTINY-Lung01 and DESTINY-Lung02 were retrospectively analyzed alongside commercially procured samples using the ODxT test and compared to the assays used for screening in these clinical trials., Results.—: Positive percent agreement (PPA) and negative percent agreement (NPA) between the ODxT Test and TruSight Tumor 170 assay when testing DESTINY-Lung01 and commercially procured samples met prespecified thresholds (PPA and NPA ≥90%) for analytical accuracy (100% and 99.1%). The ODxT Test results were highly concordant with clinical trial assays (CTAs) used in DESTINY-Lung01 (PPA and NPA, 98.0% and 100%) and DESTINY-Lung02 (PPA and NPA, 96.7% and 100%) to identify activating HER2 mutations in tumor samples. Confirmed objective response rates were similar between patients with HER2m tumors identified by the ODxT Test and by CTAs in DESTINY-Lung01 (58.3% and 54.9%) and DESTINY-Lung02 (53.6% and 53.8%). Response duration was 12.0 and 9.3 months for patients identified by the ODxT Test and CTAs, respectively, in DESTINY-Lung01., Conclusions.—: The ODxT Test detected HER2 mutations in NSCLC with high analytical and clinical accuracy and identified HER2m populations with response rates similar to populations identified by CTAs, supporting clinical utility of the ODxT Test to inform treatment decisions for HER2m NSCLC., Competing Interests: Karnoub, Pereira, and Shiga are employees of Daiichi Sankyo, Inc. Qi, Feng, and Khambata-Ford are employees of and hold stock and stock options in Daiichi Sankyo, Inc. Ha and Velasco Roth are employees of Thermo Fisher Scientific. Smit has received consulting fees paid to his institution from Daiichi Sankyo, Inc, and has participated in advisory boards for Daiichi Sankyo, Inc. Y. Goto has received research grants paid to his clinical trial group or institution from Daiichi Sankyo, Inc, speaker payments or honoraria from Thermo Fisher Scientific, and has participated in advisory boards for Daiichi Sankyo, Inc. K. Goto has received research grants paid to his institution from Daiichi Sankyo, Inc, speaker payments or honoraria from Daiichi Sankyo, Inc, and Thermo Fisher Scientific, and has participated in advisory boards for Daiichi Sankyo, Inc. De Langen has no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs., Competing Interests: Declaration of interests NPvE has received research grants from Astellas and Ipsen. NM received consultancy fees from Janssen-Cilag, Bayer, Astellas Pharma, AstraZeneca, Pfizer, and Merck Sharp and Dohme, and research funding (all paid to the institution) from Janssen-Cilag, Astellas Pharma, AstraZeneca/Merck, and Bristol Myers Squibb Foundation. KB received consultancy fees (all paid to the institution) from Merck Sharp and Dohme and Pierre Fabre. HG's institution has received research grants or compensation for patients in studies from Bayer, Boehringer Ingelheim, Deciphera, AmmaxBio, Abbisko, Springworks, Amgen, Pfizer, Novartis, and Servier. GSS received research support (all paid to the institution) from Agendia, AstraZeneca, Merck Sharp and Dohme, Novartis, Roche, and Seagen, and serves on advisory boards for Biovica and Seagen. AJdL reports financial interests and institutional research grants from Bristol Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, and AstraZeneca; and non-financial interests from Merck Serono and Roche. NWCJvdD has received research support (all paid to the institution) from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier. JJWMJ has received research support (all paid to the institution) from Novartis and Bristol Myers Squibb; serves as president for Apps for Care and Science, a non-profit foundation supported by AbbVie, Alexion, Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Janssen-Cilag, Novartis, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, and Takeda; and has received honoraria (all paid to the institution) from AbbVie, Novartis, Pfizer, and Incyte. MCM has received research support (all paid to the institution) from Beigene, consultancy fees (all paid to the institution) from Janssen-Cilag, CDR-life, BMC, and GlaxoSmithKline; fees for speakers bureau (all paid to the institution) from Siemens and Janssen-Cilag; and hospitality from Janssen-Cilag. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using 18 F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events., Methods: Four 18 F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV) mean , lymph node SUV max ) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted., Results: Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUV mean 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUV max 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUV max 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity., Conclusion: PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer., Competing Interests: Competing interests: RvdV: Research funding for Institute: Genmab B.V. TDdG: Research funding for Institute: Idera Pharmaceuticals (now Aceragen); Consultancy: GE Health, LAVA Therapeutics, Mendus (all to Institute); holds stocks from LAVA Therapeutics. GAPH: Research funding for Institute: Bristol-Myers Squibb, Seerave. Consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, Pierre Fabre. AJdL: Research funding for Institute: Bristol-Myers Squibb, MSD, Boehringer Ingelheim, AstraZeneca. Non-financial support from Merck Serono, non-financial support from Roche. CWM-vdHvO: Research funding for Institute: Bristol-Myers Squibb, Boehringer Ingelheim, GSK, Pfizer; AstraZeneca. Consultancy: GE Health Care, Novartis, Eli Lilly. IHCM, JEEP, AK, GJCZ, MCH, FEFT: No competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non-small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab., Methods: In this single-arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m 2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment., Results: Thirty-seven patients started treatment, with a median age of 65 years (range, 40-80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression-free survival was 5.5 months (95% CI, 3.7-8.3 months) and median overall survival was 16.8 months (95% CI, 10.7-25.8 months). The most common treatment-related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients., Conclusions: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction., (© 2023 American Cancer Society.)

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., (© 2023. Springer Nature Limited.)

Background: the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients., Methods: In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups., Results: A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups., Conclusions: For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib., Competing Interests: E. F. Smit reports consulting or advisory role (institution) for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, MSD Oncology, Novartis, Roche/Genentech, Seattle Genetics, Takeda; and research funding (institution) from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Roche/Genentech, outside of the submitted work. A. J. de Langen reports grants from BMS, MSD, AstraZenica, and Boehringer, and nonfinancial support from Merck Serono and Roche, outside the submitted work. N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim and Ellipses Pharma and received research grants for the institute from A.B. Science, Abbvie, Actuate Therapeutics, ADCtherapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Cresecendo, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead, GlaxoSmithKline, Incyte, InteRNA, Janssen/Johnson&Johnson, Kinate, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho, Takeda, outside of the submitted work. J. H. Beijnen is a part-time employee and (indirect) shareholder of Modra Pharmaceuticals B.V. He is (partly) patent holder of oral taxane formulations which are clinically developed by Modra Pharmaceuticals B.V. (a spin-off company of the Netherlands Cancer Institute, not related to this work). L. Lin, H. J. Barkman, and A. D. R. Huitema declare no potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Background: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R., Methods: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2., Results: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events., Conclusions: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Anti-PD-(L)1 immunotherapy has emerged as a promising treatment approach for non-small cell lung cancer (NSCLC), though the response rates remain low. Pre-treatment response prediction may improve patient allocation for immunotherapy. Blood platelets act as active immune-like cells, thereby constraining T-cell activity, propagating cancer metastasis, and adjusting their spliced mRNA content., Objective: We investigated whether platelet RNA profiles before start of nivolumab anti-PD1 immunotherapy may predict treatment responses., Methods: We performed RNA-sequencing of platelet RNA samples isolated from stage III-IV NSCLC patients before treatment with nivolumab. Treatment response was scored by the RECIST-criteria. Data were analyzed using a predefined thromboSeq analysis including a particle-swarm-enhanced support vector machine (PSO/SVM) classification algorithm., Results: We collected and processed a 286-samples cohort, separated into a training/evaluation and validation series and subjected those to training of the PSO/SVM-classification algorithm. We observed only low classification accuracy in the 107-samples validation series (area under the curve (AUC) training series: 0.73 (95% -CI: 0.63-0.84, n = 88 samples), AUC evaluation series: 0.64 (95% -CI: 0.51-0.76, n = 91 samples), AUC validation series: 0.58 (95% -CI: 0.45-0.70, n = 107 samples)), employing a five-RNAs biomarker panel., Conclusions: We concluded that platelet RNA may have minimally discriminative capacity for anti-PD1 nivolumab response prediction, with which the current methodology is insufficient for diagnostic application.

Purpose: Treatment advancements have improved life expectancy for adolescents and young adults (AYAs) with an uncertain and/or poor cancer prognosis (UPCP) and change clinical practice. This improved survival requires a different approach and specific expertise to meet the needs of this group. The aim of this study is to explore the health care experiences of AYAs with a UPCP., Methods: We conducted a multicenter qualitative study using semi-structured interviews and elements of the grounded theory by Corbin and Strauss., Results: Interviews were conducted with 46 AYAs with a UPCP. They were on average 33.4 years old (age range 23-44), and most of them were woman (63%). Additionally, five AYAs with a UPCP participated as AYA research partners in two focus groups. They were on average 31.8 years old and four of them were woman. AYAs with a UPCP reported four pillars for a satisfied healthcare experience: (1) trust, (2) tailored communication, (3) holistic empathic open attitude, and (4) care being offered (pro-)actively. They reported both optimal and suboptimal experiences about distrust based on a delay in diagnostic trajectory, lack of tailored communication and discussion of sensitive topics, preference for a holistic approach, and struggles with finding the way to get additional healthcare support., Conclusion: For AYAs with a UPCP, it is important that both age-specific issues and issues related to the UPCP are understood and addressed; however, this seems not yet optimally implemented in clinical practice. This emphasizes the importance of providing this patient group with tailored care incorporating both aspects. Healthcare professionals need to be supported with training and tools to understand the healthcare needs of AYAs with a UPCP. AYAs can be empowered to take more control over their own healthcare needs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: 89 Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([ 89 Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [ 89 Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses., Method: 89 Zr-immuno-PET data from five [ 89 Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2-3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (K i ). To identify target engagement, K i values were compared to ns-baseline K i values previously reported, and the effect of increasing mass doses on K i was investigated., Results: All mAbs, except ipilimumab, showed K i values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing K i values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed K i values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. K i values were near zero in brain tissue for all mass doses of all mAbs., Conclusion: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the K i values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.

Purpose: Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2-mutant ( HER2 m; defined as single-nucleotide variants and exon 20 insertions) metastatic non-small-cell lung cancer (mNSCLC)., Methods: DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2 m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review., Results: One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively., Conclusion: T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.

Activating EGFR mutations are commonly observed in non-small cell lung cancer (NSCLC). About 4-10 % of all activating epidermal growth factor receptor (EGFR) mutations are heterogenous in-frame deletion and/or insertion mutations clustering within exon 20 (EGFRex20+). NSCLC patients with EGFRex20+ mutations are treated as a single disease entity, irrespective of the type and location of the mutation. Here, we provide a comprehensive assessment of the literature reporting both in vitro and clinical drug sensitivity across different EGFRex20+ mutations. The activating A763_Y764insFQEA mutation has a better tumor response in comparison with mutations in the near- and far regions directly following the C-helix and should therefore be treated differently. For other EGFRex20+ mutations marked differences in treatment responses have been reported indicating the need for a classification beyond the exon-based classification. A further classification can be achieved using a structure-function modeling approach and experimental data using patient-derived cell lines. The detailed overview of TKI responses for each EGFRex20+ mutation can assist treating physicians to select the most optimal drug for individual NSCLC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: In patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung (NSCLC) chemotherapy remains standard of care after progression on EGFR-tyrosine kinase inhibitors (TKIs). With the development of anti-angiogenic agents and immune checkpoint inhibitors the landscape of systemic regimens has changed significantly. This cohort study aims to evaluate the efficacy of chemotherapy regimens after progression on EGFR-TKI in a European population., Material and Methods: All consecutive patients treated with chemotherapy after progression on EGFR-TKI for EGFR-mutated NSCLC, were identified in two tertiary centers in the Netherlands. Data on best response, progression free survival (PFS) and overall survival (OS) were extracted from medical records., Results: In total, 171 lines of chemotherapy were identified: platinum/pemetrexed (PP, n = 95), carboplatin/paclitaxel/bevacizumab/atezolizumab (CPBA, n = 32), paclitaxel/bevacizumab (PB, n = 36) and carboplatin/paclitaxel/bevacizumab (CPB, n = 8). Of the 171 lines, 106 were given as first-line after EGFR-TKI. Median PFS did not differ significantly between the first-line regimens (p = 0.50), with the highest PFS in PP (5.2 months [95% CI 4.5-5.9]) and CPBA (5.9 months [95% CI 3.8-80]). The majority of the PB group (n = 32) received this regimen in a second- or later line with a median PFS of 4.9 months (95% CI 3.3-6.6). First-line regimens had a median OS of 15.3 months (95% CI 11.6-18.9) with no significant difference between regimens (p = 0.85)., Conclusion: After progression on EGFR-TKI, patients with EGFR-mutated NSCLC show substantial benefit on different chemotherapy regimens. In particular, favorable outcomes were seen in patients treated with PP and CPBA as first-line chemotherapy, and PB in further lines of chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.M.J. Steendam reports receiving institutional fees from Boehringer Ingelheim, Roche and Eli Lilly; outside the current work. S.K. Badrising reports receiving institutional fees from Pfizer; outside the current work. M.S. Paats reports receiving institutional fees from AstraZeneca, Bayer, Eli Lilly, Janssen, Novartis, Pfizer, Roche and Takeda; outside the current work. J.G.J.V. Aerts reports receiving advisory board and speakers fees from Eli-Lilly, BMS, MSD, Astra-Zeneca, Bayer, Amphera and is a stock owner of Amphera; outside the current work. A.J. de Langen reports institutional fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Merus; outside the current work. A.C Dingemans reports receiving institutional fees from Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Janssen, Chiezi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, Sanofi and Daiichi; outside the current work. S.M. Ernst reports no disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Better biomarkers for programmed death - (ligand) 1 (PD-(L)1) checkpoint blockade in non-small cell lung cancer (NSCLC) are needed. We explored the predictive value of early response evaluation using Fluor-18-deoxyglucose positron emission tomography and pre- and on-treatment flowcytometric T-cell profiling in peripheral blood and tumor-draining lymph nodes (TDLN). The on-treatment evaluation was performed 7-14 days after the start of PD-1 blockade in NSCLC patients. These data were related to (pathological) tumor response, progression-free survival, and overall survival (OS). We found that increases in total lesion glycolysis (TLG) had a strong reverse correlation with OS ( r = -0.93, p  = 0.022). Additionally, responders showed decreased progressors and increased Treg frequencies on-treatment. Frequencies of detectable PD-1-expressing CD8 + T cells decreased in responders but remained stable in progressors. This was especially found in the TDLN. Changes in activated Treg rates in TDLN were strongly but, due to low numbers of data points, non-significantly correlated with ΔTLG and reversely correlated with OS., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Introduction: Patient-reported smoking history is frequently used as a stratification factor in NSCLC-directed clinical research. Nevertheless, this classification does not fully reflect the mutational processes in a tumor. Next-generation sequencing can identify mutational signatures associated with tobacco smoking, such as single-base signature 4 and indel-based signature 3. This provides an opportunity to redefine the classification of smoking- and nonsmoking-associated NSCLC on the basis of individual genomic tumor characteristics and could contribute to reducing the lung cancer stigma., Methods: Whole genome sequencing data and clinical records were obtained from three prospective cohorts of metastatic NSCLC (N = 316). Relative contributions and absolute counts of single-base signature 4 and indel-based signature 3 were combined with relative contributions of age-related signatures to divide the cohort into smoking-associated ("smoking high") and nonsmoking-associated ("smoking low") clusters., Results: The smoking high (n = 169) and smoking low (n = 147) clusters differed considerably in tumor mutational burden, signature contribution, and mutational landscape. This signature-based classification overlapped considerably with smoking history. Yet, 26% of patients with an active smoking history were included in the smoking low cluster, of which 52% harbored an EGFR/ALK/RET/ROS1 alteration, and 4% of patients without smoking history were included in the smoking high cluster. These discordant samples had similar genomic contexts to the rest of their respective cluster., Conclusions: A substantial subset of metastatic NSCLC is differently classified into smoking- and nonsmoking-associated tumors on the basis of smoking-related mutational signatures than on the basis of smoking history. This signature-based classification more accurately classifies patients on the basis of genome-wide context and should therefore be considered as a stratification factor in clinical research., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (C min,SS ) were below 435 ng/mL. This may suggest that patients should have an alectinib C min,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM., Methods: ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib C min,SS < 435 ng/mL, arm A will receive increased doses of alectinib till C min,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition., Discussion: The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05525338., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. BM: nothing to disclose in relationship to this manuscript. Outside of current manuscript: BM received the AACR-Bristol Myers Squibb Scholar-in-Training award 2022 travel support to attend the AACR Annual Meeting 2022. MP has no relationship to disclose in relation to this manuscript. MP attended advisory boards and/or provided lectures for: Takeda, Eli Lilly, Bayer, Roche, AstraZeneca, Novartis, Janssen Pharmaceuticals and Pfizer; for which the institute received honoraria. ESc reports lectures for Bio-Rad, Seracare, Novartis, Roche, Biocartis, Illumina, Lilly, Janssen Cilag, Pfizer, AstraZeneca and Agena Bioscience; consultant in advisory boards for MSD/Merck, GSK, AstraZeneca, Astellas Pharma, Roche, Pfizer, Novartis, Bayer, BMS, Lilly, Amgen, Biocartis, Illumina, Agena Bioscience, Janssen Cilag Johnson&Johnson, Diaceutics, CC Diagnostics; and received research grants from Pfizer, Biocartis, Invitae-ArcherDX, AstraZeneca, Agena Bio-science, BMS, Bio-Rad, Roche, Boehringer Ingelheim honoria paid to UMCG account. WT: nothing to disclose in relationship to this manuscript. Outside of current manuscript: WT reports consultant in advisory boards for MSD/Merck, and BMS all payment to UMCG. DT reports grants from Chiesi and advisory boards from Sanquin and PureIMS, all outside the submitted work. Payments were made to the UMCG. JB reports consultancy fees, speaking fees and/or research grants from Aardex, AstraZeneca, Chiesi, European Commission COST Action 19132 “ENABLE”, GSK, Novartis, Teva, Trudell Medical and Vertex, all paid to his employer UMCG and unrelated to this study. AL reports grants from AstraZeneca, BMS, MSD, Boehringer Ingelheim, and non-financial support from Merck Serono and Roche, all outside the submitted work. SH: research grant and advisory board: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, GSK, MSD, Novartis, Roche, Takeda, and Xcovery. LH: No relationship to disclose in relation to this manuscript. Outside of current manuscript: research funding Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda all institution, Beigene under negotiation; advisory board: BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer Ingelheim, Amgen, Janssen all institution, Roche one time self; speaker: MSD, Lilly institution; travel/conference reimbursement: Roche Genentech self; mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Benecke, Medtalks, VJOncology self, high5oncology institution; interview sessions funded by Roche Genentech, Bayer, Lilly institution; local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD, Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Pharmaceuticals, Mirati, Abbvie, Gilead. MH has nothing to disclose in relationship to this manuscript. Outside of current manuscript: research grants by AZD, Bristol Myers Squibb, Merck, MSD, Novartis, Pfizer and Roche, all paid to the institute. AD: nothing to disclose in relationship to this manuscript. Outside of current manuscript: research funding from Amgen, Astra Zeneca, Chiesi, Eli Lilly, Janssen sponsored symposium, Pfizer, Takeda. AD attended advisory boards or Steering committee of Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Pharmamar, Sanofi, Roche. All paid to the institute. RM: nothing to disclose in relationship to this manuscript. Research grants all paid to the institute during the last 2 years from Astellas, Bayer, Boehringer-Ingelheim, Cristal-Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, Servier. ESm: nothing to disclose in relationship to this manuscript. Attended advisory boards for Astra Zeneca, BMS, Bayer, Boehringer Ingelheim, DSI, Eli Lilly, MSD, Merck, Novartis, Pfizer, Takeda, Roche Genentech. ESm received research funding from: Astra Zeneca, BMS, MSD, Merck, Roche Genentech. All of the above institutional, no personal financial interests. NS provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, Luszana, Cogent Biosciences. NS received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Eisai, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. AW reports grants and advisory board from AstraZeneca, grants and advisory board from Boehringer-Ingelheim, advisory board from Janssen, advisory board from Novartis, grants and advisory board from Pfizer, grants and advisory board from Roche, grants and advisory board from Takeda, all outside the submitted work. All payment to the UMCG., (Copyright © 2023 Meertens, Muntinghe-Wagenaar, Sikkema, Lopez-Yurda, Retèl, Paats, Ter Heine, Schuuring, Timens, Touw, van Boven, de Langen, Hashemi, Hendriks, Croes, van den Heuvel, Dingemans, Mathijssen, Smit, Huitema, Steeghs and van der Wekken.)

Background: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRAS G12C . We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRAS G12C mutation who had been previously treated with other anticancer drugs., Methods: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRAS G12C -mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRAS G12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRAS G12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m 2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting., Findings: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%])., Interpretation: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRAS G12C mutation and who had been previously treated with other anticancer drugs., Funding: Amgen., Competing Interests: Declaration of interests AJdL reports financial interests, institutional, research grant from BMS, MSD, Boehringer, AstraZeneca; non-financial interests, other from Merck Serono, Roche. MLJ reports financial interests, institutional, research grant from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda Therapeutics, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, Tmunity Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics, Black Diamond, Carisma Therapeutics, Elicio Therapeutics, EQRx, Immunitas Therapeutics, Kartos Therapeutics, Mirati Therapeutics, Palleon Pharmaceuticals, Rain Therapeutics; financial interests, institutional, consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, IDEAYA Biosciences, iTeos Therapeutics, Janssen, Lilly, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, VBL Therapeutics, Takeda Pharmaceuticals, Arrivant, Pyramid Biosciences, Revolution Medicines, Seagen. JM reports financial interests, personal fees from Amgen, AstraZeneca, Roche, Pierre Fabre, Pfizer; financial interests, institutional, research grant from AstraZeneca, Roche, Pierre Fabre; advisory board for Merck, Roche, AstraZeneca, MSD, BMS, Pfizer, Hengrui Therapeutics, Daiichi, Boehringer, Pierre Fabre, Amgen. A MCD reports other, institutional, advisory board for Amgen, Bayer, Boehringer Ingelheim, Roche, Sanofi; other, institutional, invited speaker for AstraZeneca, Janssen, Eli Lilly, Pfizer, Takeda; financial interests, institutional, research grant from Amgen; financial interests, institutional, principal investigator, local PI for Amgen, Daiichi, JNJ, Eli Lilly, Mirati Therapeutics; financial interests, institutional, principal investigator, coordinating PI for Roche; financial interests, institutional, other, steering committee member for Roche. GM reports financial interests, personal, other, consulting fees from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Pierre Fabre Greece, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, payment for expert testimony from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Pierre Fabre Greece, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, support for attending meetings and/or travel from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Pierre Fabre Greece, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, participation on a data safety monitoring board or advisory board for Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, leadership or fiduciary role in other board, society, committee or advocacy group, unpaid for European Society for Medical Oncology working groups (Educational Publication Working Group, Adolescents and Young Adults working group); financial interests, institutional, principal investigator for Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Gilead Greece, GSK Greece, Amgen Hellas, Sanofi Greece. MP reports financial interests, personal, advisory board for AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eisei, MSD, Novartis, Pfizer, Roche, Takeda, Merck, Sanofi, Bayer, Amgen; financial interests, personal, other, travel grant from AstraZeneca, BMS, Boehringer Ingelheim, Roche, Takeda, Vifor; financial interests, personal, speaker fees from Janssen, Nestle. JW reports financial interests, personal, advisory board, lectures fees from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Merck, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Turning Point, Nuvalent; financial interests, institutional, research grant from BMS, Janssen, Novartis, Pfizer. MS reports financial interests, institutional, research grant from AstraZeneca, Bristol Myers Squibb; financial interests, personal, consulting fees from Amgen, AstraZeneca, BIOCAD, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda; financial interests, personal, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis; financial interests, personal, support for attending meetings and/or travel from BIOCAD, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Novartis; financial interests, personal, participation on a data safety monitoring board or advisory board for Amgen, Bristol Myers Squibb, Novartis, Sanofi, GlaxoSmithKline, Merck Serono. HL reports financial interests, other, personal fees from Daiichi Sankyo, AstraZeneca, Pfizer, Novartis, Amgen, MSD, Roche, BMS, Eli Lilly, Boehringer Ingelheim. FS reports financial interests, personal, other, consulting fees from AstraZeneca, Amgen, Novartis, BeiGene Guardant Health, BerGenBio, Navire Pharma, Tango Therapeutics, Calithera Biosciences; financial interests, personal, other, lecture fees from European Society for Medical Oncology, Japanese Lung Cancer Society, Medscape, Intellisphere, VSPO McGill Universite de Montreal, RV Mais Promoção Eventos Ltda, MJH Life Sciences, IDEOlogy Health, MI&T, PER, LLC, CURIO; financial interests, personal, other, fees for travel, food and beverage from Dava Oncology, Tango Therapeutics, American Association for Cancer Research, International Association for the Study of Lung Cancer (IASLC), MJH Life Sciences, IDEOlogy Health, MI&T, PER, LLC, CURIO; financial interests, personal, stocks/shares, stock or stock options for BioNTech SE, Moderna (completed 2020); financial interests, institutional, research grant from Amgen, Mirati Therapeutics, Revolution Medicines, Pfizer, Novartis, Merck & Co; participation on a data safety monitoring board or advisory board for AstraZeneca, Amgen, Novartis, BeiGene, Guardant Health, BerGenBio; Calithera Biosciences. YY reports no relationships to disclose. S-WK reports no relationships to disclose. HL reports financial interests, personal, other, consulting fees from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, GSK, Merck, Amgen, Boehringer, Pfizer, Lilly; financial interests, personal, other, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, AbbVie, GSK, Amgen, Boehringer, Pfizer, Lilly; financial interests, personal, other, payment for expert testimony from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, GSK, Amgen, Boehringer, Pfizer, Lilly; financial interests, personal, other, support for attending meetings and/or travel from Roche, Novartis, BMS, MSD, AstraZeneca, GSK, Amgen, Boehringer, Pfizer; financial interests, personal, participation on a data safety monitoring board or advisory board for Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, GSK, Amgen, Boehringer, Pfizer, Lilly; other, personal, leadership role, W4O Core Committee – Unpaid for European Society for Medical Oncology; other, personal, leadership role, President of the Scientific Committee and Member of the Board of Directors – Unpaid for Hellenic Cooperative Oncology Group; other, personal, leadership role, member of board of directors – unpaid for Hellenic Foundation for Cancer Research, FairLife LCC; Other, personal, leadership role, legal representative member of board of directors - unpaid for W4O-Hellas; financial interests, personal and institutional, principal investigator, pi in sponsored clinical trials, personal and institutional fees from Bristol Myers Squibb, Boehringer Ingelheim, Roche, AbbVie, Lilly, Novartis, AstraZeneca, Amgen, PPD, Parexel ILR, Qualitis, Health Data Specialist. SN reports financial interests, personal, advisor/speaker bureau for AstraZeneca, BI, MSD, Roche, Sanofi, Pfizer, Takeda, Thermo Fisher, Novartis; financial interests, personal, speaker bureau for BeiGene. AJvdW reports financial interests, institutional, research grant from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, Takeda; financial interests, fees to institution from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, Takeda, Janssen Cilag, Lilly, Amgen, Merck. YC reports other, personal, speaker faculty for Amgen, AstraZeneca, Bristol Myers Squibb, Guardant Health, Jazz Pharmaceuticals, Pfizer, Takeda; other, personal, advisory board for AstraZeneca, Bristol Myers Squibb, Mirati Therapeutics; financial interests, institutional, principal investigator, local PI for Amgen, AstraZeneca, Bristol Myers Squibb, EMD/Serono, Helsinn, Ipsen, Merck. SP reports financial interests, institutional, support for study conduct and medical writing from AstraZeneca; financial interests, institutional, principal investigator, coordinating PI for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, Roche/Genentech. Financial interests, institutional, consulting fees from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, PeerView, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody; financial interests, institution, other, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati Therapeutics, Novartis, PeerView, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda; financial interests, institutional, other, support for attending meetings and/or travel from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, Roche/Genentech, Takeda; financial interests, institutional, other, participation on a data safety monitoring board or advisory board for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, PeerView, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. EF reports financial interests, institutional, research grant from Merck Healthcare KGaA (grant for oncology innovation), Fundación Merck Salud; financial interests, institutional, consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Sanofi, Takeda, BerGenBio; financial interests, institutional, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology; other financial/non-financial interests, board member for Grífols. BJS reports financial interests, institutional, funding, institutional funding for conduct of clinical trial from Amgen; financial interests, personal, advisory board/honoraria from Amgen, Roche-Genentech, Novartis, Pfizer, AstraZeneca, Bristol Myers Squibb, Takeda, Eli Lilly, Merck Sharp Dohme, Janssen. SSR reports financial interests, personal, research grant from Amgen, AstraZeneca; financial interests, personal, advisory board for AstraZeneca, Mirati Therapeutics, Merck, BMS, GlaxoSmithKline, Genmab. CD reports no relationships to disclose. CL reports financial interests, personal, advisory board from Amgen; financial interests, personal, educational presentation/workshop from Amgen; financial interests, institutional, advisory board for CBPartners; non-financial interests, institutional, principal investigator, coordinating PI for Amgen, BI, Mirati Therapeutics, Revolution Medicines, Roche; non-financial interests, institutional, principal investigator, local PI Apollomics. CGF reports financial interests, other, consulting fees from AstraZeneca, Janssen; advisory board for IASCL; financial interests, personal, stocks/shares, stock or stock options in Oncoclínicas - Brazil. NB reports financial interests, other, consulting fees/honoraria from Amgen. CCO, YW, BM, TV, GN, BS report financial interests, personal, current or former full-time employment, employee and stockholder/shareholder in Amgen. DW reports financial interests, personal, invited speaker, advisory event, travel for BMS; financial interests, personal, invited speaker, advisory event for AstraZeneca, Janssen, EMD Serono; financial interests, personal, invited speaker, advisory event, consultant for Amgen, Merck; financial interest, personal, advisory event, consultant for Jazz Pharmaceuticals, Fresenius Kbi; financial interests, personal, advisory event for Pfizer, Mirati Therapeutics, Regeneron/Sanofi; financial interests, personal, advisory event for Exelixis, Eisai, Pfizer, Mirati Therapeutics, Regeneron/Sanofi, Lilly, Sanofi, Astellas, Gilead. LPA reports financial interests, research grant from MSD, AstraZeneca, Pfizer, BMS; financial interests, consulting fees from Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati Therapeutics, GSK, Janssen, Takeda, Daiichi Sankyo; financial interests, payment/honoraria for lectures, presentations, speakers bureau from AstraZeneca, Janssen, Merck, Mirati Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: EGFR tyrosine kinase inhibitor improved the survival of patients with metastatic EGFR mutation-positive ( EGFRm+ ) NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found on progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with trastuzumab-emtansine (T-DM1) could reinduce tumor responses., Methods: In this multicenter, single-arm, phase 1-2 study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (intravenously) every 3 weeks and osimertinib 80 mg once a day. Primary end points were objective response rate (ORR) at 12 weeks and safety. Responses were assessed every 6 weeks (Response Evaluation Criteria in Solid Tumors 1.1). Sample size was calculated using Simon's two-stage minimax design (H0 = 41%, H1 > 55%, 80% power, one-sided type I error 10%: a ORR 16 of 36 was needed to proceed to 58 patients)., Results: From January 2019 to April 2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1 of 27). Median progression-free survival was 2.8 months (95% confidence interval: 1.4-4.6 mo). Most frequent treatment-related adverse events of any grade were fatigue, diarrhea, and nausea, among these, grade 3 in four patients. There were no grade 4 or 5 therapy-related adverse events., Conclusions: TRAEMOS (Trastuzumab-Emtansine and Osimertinib) is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared with cytotoxic chemotherapy; but treatment revealed limited efficacy. Further clinical evaluation of this regimen is not warranted., (© 2023 The Authors.)

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC)., Materials and Methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity., Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity., Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR -mutated NSCLC at the expense of more toxicity., Competing Interests: Conflict of interest: R.G.P. Gijtenbeek has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: V. van der Noort has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: J.G.J.V. Aerts has received support for the present manuscript from Roche, Lilly and Amgen; consulting fees from MSD, BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca and BIOCAD, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from MSD, BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca and BIOCAD, outside the submitted work; and patents planned, issued or pending for an allogenic tumour cell lysate, Amphera, combination immunotherapy in cancer, and a biomarker for immunotherapy, unrelated to this submission. Conflict of interest: J.A. Staal-van den Brekel has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: E.F. Smit has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca and Bristol-Myers Squibb, outside the submitted work; and consulting fees from Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol-Myers Squibb, Merck KGaA, MSD Oncology, Takeda, Bayer, Novartis, Daiichi Sankyo and Seattle Genetics, outside the submitted work. Conflict of interest: F.H. Krouwels has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: F.A. Wilschut has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: T.J.N. Hiltermann has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts received from Roche, BMS and AstraZeneca, outside the submitted work; consulting fees received from Roche, BMS, AstraZeneca and MSD, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from BMS, outside the submitted work. Conflict of interest: W. Timens has received support for the present manuscript from Roche, Lilly and Amgen; and consulting fees received from Merck Sharp Dohme and Bristol-Myers-Squibb, outside the submitted work; and is a board member of the Dutch Society of Pathology and a member of the Council for Research and Innovation of the Federation of Medical Specialists. Conflict of interest: E. Schuuring has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from Abbott, Biocartis, Astrazeneca, Invitae/Archer, Bayer, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics and Boehringer Ingelheim, outside the submitted work; consulting fees from MSD/Merck, AstraZeneca, Roche, Novartis, Bayer, BMS, Lilly, Amgen, Illumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson&Johnson) and Astellas Pharma, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bio-Rad, Seracare, Roche, Biocartis, Lilly, Agena Bioscience and Illumina, outside the submitted work; and support for attending meetings and/or travel from BioRad and Biocartis, outside the submitted work; and is an unpaid board member of the Dutch Society of Pathology, the European Society of Pathology and the European Liquid Biopsy Society. Conflict of interest: J.D.J. Janssen has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: M. Goosens has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: P.M. van den Berg has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: A.J. de Langen reports grants from BMS, MSD, Boehringer and AstraZeneca, and nonfinancial support from Merck Serono and Roche, outside the submitted work. Conflict of interest: J.A. Stigt has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: B.E.E.M. van den Borne has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: H.J.M. Groen has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from Roche and Boehringer Ingelheim, outside the submitted work; and consulting fees from Lilly, Novartis, Roche/Genentech and AstraZeneca, outside the submitted work. Conflict of interest: W.H. van Geffen has received support for the present manuscript from Roche, Lilly and Amgen; has unpaid roles for ERS and NVALT, outside the submitted work; and there have been trials run by his department funded by Roche and Amgen. Conflict of interest: A.J. van der Wekken has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda and Roche, outside the submitted work; consulting fees from AstraZeneca, Novartis, Boehringer Ingelheim, Roche, Janssen, Pfizer, Lilly, Takeda and Merck, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Pfizer, outside the submitted work; and support for attending meetings and/or travel received from Lilly, outside the submitted work; and has a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for CPCT, outside the submitted work., (Copyright ©The authors 2022.)

The current increase in number and diversity of targeted anticancer agents poses challenges to the logistics and timeliness of molecular diagnostics (MolDx), resulting in underdiagnosis and treatment. Whole-genome sequencing (WGS) may provide a sustainable solution for addressing current as well as future diagnostic challenges. The present study therefore aimed to prospectively assess feasibility, validity, and value of WGS in routine clinical practice. WGS was conducted independently of, and in parallel with, standard of care (SOC) diagnostics on routinely obtained tumor samples from 1,200 consecutive patients with metastatic cancer. Results from both tests were compared and discussed in a dedicated tumor board. From 1,200 patients, 1,302 samples were obtained, of which 1,216 contained tumor cells. WGS was successful in 70% (854/1,216) of samples with a median turnaround time of 11 days. Low tumor purity (&lt;20%) was the main reason for not completing WGS. WGS identified 99.2% and SOC MolDx 99.7% of the total of 896 biomarkers found in genomic regions covered by both tests. Actionable biomarkers were found in 603/848 patients (71%). Of the 936 associated therapy options identified by WGS, 343 were identified with SOC MolDx (36.6%). Biomarker-based therapy was started in 147 patients. WGS revealed 49 not previously identified pathogenic germline variants. Fresh-frozen, instead of formalin-fixed and paraffin-embedded, sample logistics were easily adopted as experienced by the professionals involved. WGS for patients with metastatic cancer is well feasible in routine clinical practice, successfully yielding comprehensive genomic profiling for the vast majority of patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting., Methods: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C min,pred ) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship., Results: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 - 19.1) months and 9.3 (95% CI: 7.2 - 11.1) months for patients with C min,pred  < 166 µg/L and C min,pred  ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a C min,pred  < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 - 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 - 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91)., Conclusion: In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 + ) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors., Methods: The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs)., Results: From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47-87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0-3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771&#95;H773dup) (n = 3) and p.(A767&#95;V769dup) (n = 3). The ORR was 28% (95% CI, 12-49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7-27.6). The median PFS was 6.8 months (95% CI, 4.6-9.1) and the median OS was 15.2 months (95% CI, 14.3-16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%)., Conclusion: The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'., Methods: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained., Results: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772&#95;A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed., Conclusion: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

PET radiomics applied to oncology allow the measurement of intratumoral heterogeneity. This quantification can be affected by image protocols; hence, there is an increased interest in understanding how radiomic expression on PET images is affected by different imaging conditions. To address that interest, this study explored how radiomic features are affected by changes in 18 F-FDG uptake time, image reconstruction, lesion delineation, and radiomic binning settings. Methods: Ten non-small cell lung cancer patients underwent 18 F-FDG PET on 2 consecutive days. On each day, scans were obtained at 60 and 90 min after injection and reconstructed following EARL version 1 and with point-spread-function resolution modeling (PSF-EARL2). Lesions were delineated with an SUV threshold of 4.0, with 40% of SUV max , and with a contrast-based isocontour. PET image intensity was discretized with both a fixed bin width (FBW) and a fixed bin number before the calculation of the radiomic features. Repeatability of features was measured with the intraclass correlation coefficient, and the change in feature value over time was calculated as a function of its repeatability. Features were then classified into use-case scenarios based on their repeatability and susceptibility to tracer uptake time. Results: With PSF-EARL2 reconstruction, 40% of SUV max lesion delineation, and FBW intensity discretization, most features (94%) were repeatable at both uptake times (intraclass correlation coefficient > 0.9), 35% being classified for dual-time-point use cases as being sensitive to changes in uptake time, 39% were classified for cross-sectional studies with an unclear dependency on time, 20% were classified for cross-sectional use while being robust to uptake time changes, and 6% were discarded for poor repeatability. EARL version 1 images had 1 fewer repeatable feature (neighborhood gray-level different matrix coarseness) than PSF-EARL2; the contrast-based delineation had the poorest repeatability of the delineation methods, with 45% of features being discarded; and fixed bin number resulted in lower repeatability than FBW (45% and 6% of features were discarded, respectively). Conclusion: Repeatability was maximized with PSF-EARL2 reconstruction, lesion delineation at 40% of SUV max , and FBW intensity discretization. On the basis of their susceptibility to uptake time, radiomic features were classified into specific non-small cell lung cancer PET radiomics use cases., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Better biomarkers are needed to predict treatment outcome in non-small cell lung cancer (NSCLC) patients treated with anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors. PD-L1 immunohistochemistry has limited predictive value, possibly because of tumor heterogeneity of PD-L1 expression. Noninvasive PD-L1 imaging using 89 Zr-durvalumab might better reflect tumor PD-L1 expression. Methods: NSCLC patients eligible for second-line immunotherapy were enrolled. Patients received 2 injections of 89 Zr-durvalumab: one without a preceding dose of unlabeled durvalumab (tracer dose only) and one with a preceding dose of 750 mg of durvalumab, directly before tracer injection. Up to 4 PET/CT scans were obtained after tracer injection. After imaging acquisition, patients were treated with 750 mg of durvalumab every 2 wk. Tracer biodistribution and tumor uptake were visually assessed and quantified as SUV, and both imaging acquisitions were compared. Tumor tracer uptake was correlated with PD-L1 expression and clinical outcome, defined as response to durvalumab treatment. Results: Thirteen patients were included, and 10 completed all scheduled PET scans. No tracer-related adverse events were observed, and all patients started durvalumab treatment. Biodistribution analysis showed 89 Zr-durvalumab accumulation in the blood pool, liver, and spleen. Serial imaging showed that image acquisition 120 h after injection delivered the best tumor-to-blood pool ratio. Most tumor lesions were visualized with the tracer dose only versus the coinjection imaging acquisition (25% vs. 13.5% of all lesions). Uptake heterogeneity was observed within (SUV peak range, 0.2-15.1) and between patients. Tumor uptake was higher in patients with treatment response or stable disease than in patients with disease progression according to RECIST 1.1. However, this difference was not statistically significant (median SUV peak , 4.9 vs. 2.4; P = 0.06). SUV peak correlated better with the combined tumor and immune cell PD-L1 score than with PD-L1 expression on tumor cells, although neither was statistically significant ( P = 0.06 and P = 0.93, respectively). Conclusion: 89 Zr-durvalumab was safe, without any tracer-related adverse events, and more tumor lesions were visualized using the tracer dose-only imaging acquisition. 89 Zr-durvalumab tumor uptake was higher in patients with a response to durvalumab treatment but did not correlate with tumor PD-L1 immunohistochemistry., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Patients with non-small cell lung cancer (NSCLC) driven by activating epidermal growth factor receptor (EGFR) mutations are best treated with therapies targeting EGFR, i.e., tyrosine kinase inhibitors (TKI). Radiolabeled EGFR-TKI and PET have been investigated to study EGFR-TKI kinetics and its potential role as biomarker of response in NSCLC patients with EGFR mutations (EGFRm). In this study we aimed to compare the biodistribution and kinetics of three different EGFR-TKI, i.e., 11 C-erlotinib, 18 F-afatinib and 11 C-osimertinib., Methods: Data of three prospective studies and 1 ongoing study were re-analysed; data from thirteen patients (EGFRm) were included for 11 C-erlotinib, seven patients for 18 F-afatinib (EGFRm and EGFR wild type) and four patients for 11 C-osimertinib (EGFRm). From dynamic and static scans, SUV and tumor-to-blood (TBR) values were derived for tumor, lung, spleen, liver, vertebra and, if possible, brain tissue. AUC values were calculated using dynamic time-activity-curves. Parent fraction, plasma-to-blood ratio and SUV values were derived from arterial blood data. Tumor-to-lung contrast was calculated, as well as (background) noise to assess image quality., Results: 11 C-osimertinib showed the highest SUV and TBR (AUC) values in nearly all tissues. Spleen uptake was notably high for 11 C-osimertinib and to a lesser extent for 18 F-afatinib. For EGFRm, 11 C-erlotinib and 18 F-afatinib demonstrated the highest tumor-to-lung contrast, compared to an inverse contrast observed for 11 C-osimertinib. Tumor-to-lung contrast and spleen uptake of the three TKI ranked accordingly to the expected lysosomal sequestration., Conclusion: Comparison of biodistribution and tracer kinetics showed that 11 C-erlotinib and 18 F-afatinib demonstrated the highest tumor-to-background contrast in EGFRm positive tumors. Image quality, based on contrast and noise analysis, was superior for 11 C-erlotinib and 18 F-afatinib (EGFRm) scans compared to 11 C-osimertinib and 18 F-afatinib (EGFR wild type) scans.

The tumor programmed death ligand 1 (PD-L1) proportion score is the current method for selecting non-small cell lung cancer (NSCLC) patients for single-agent treatment with pembrolizumab, a programmed cell death 1 (PD-1) monoclonal antibody. However, not all patients respond to therapy. Better understanding of in vivo drug behavior may help in the selection of patients who will benefit the most. Methods: NSCLC patients eligible for pembrolizumab monotherapy as first- or later-line therapy were enrolled. Patients received 2 injections of 89 Zr-pembrolizumab, 1 without a preceding dose of pembrolizumab and 1 with a preceding dose of 200 mg of pembrolizumab, directly before tracer injection. Up to 4 PET/CT scans were obtained after tracer injection. After imaging acquisition, patients were treated with 200 mg of pembrolizumab every 3 wk. Tumor uptake and tracer biodistribution were visually assessed and quantified as the SUV. Tumor tracer uptake was correlated with PD-1 and PD-L1 expression and response to pembrolizumab treatment. Results: Twelve NSCLC patients were included. One patient experienced grade 3 myalgia after tracer injection. 89 Zr-pembrolizumab was observed in the blood pool, liver, and spleen. Tracer uptake was visualized in 47.2% of 72 tumor lesions measuring ΒΧΡ20 mm in the long-axis diameter, and substantial uptake heterogeneity was observed within and between patients. Uptake was higher in patients with a response to pembrolizumab treatment ( n = 3) than in patients without a response ( n = 9), although this finding was not statistically significant (median SUV peak , 11.4 vs. 5.7; P = 0.066). No significant correlations were found with PD-L1 or PD-1 immunohistochemistry. Conclusion: 89 Zr-pembrolizumab injection was safe, with only 1 grade 3 adverse event-possibly immune-related-in 12 patients. 89 Zr-pembrolizumab tumor uptake was higher in patients with a response to pembrolizumab treatment but did not correlate with PD-L1 or PD-1 immunohistochemistry., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: With the introduction of tyrosine kinase inhibitors and systemic antibodies, including immune checkpoint inhibitors, the survival of advanced-stage cancer patients has improved for many tumor types. These patients are increasingly referred for radiotherapy, but it is unclear whether radiotherapy combined with these drugs is safe. No international guidelines exist on whether or how to combine these drugs with radiotherapy. Therefore, we investigated the current clinical practice in the Netherlands regarding hypofractionated radiotherapy in patients using targeted drugs and immunotherapy., Materials and Methods: We sent a survey to all 21 Dutch radiotherapy institutes. Dedicated radiation oncologists, medical oncologists and pulmonologists were asked to fill out the survey. The questions explored their familiarity with the combination of targeted drugs and immunotherapy with radiotherapy, the encountered clinical difficulties and factors influencing treatment decisions., Results: The survey was filled out by 54 respondents from 19 different institutes. The median annual number of patients per radiation oncologist referred for radiotherapy when using targeted drugs or immunotherapy was 10 and 15, respectively. Despite this high number, only 11% of the radiation oncologists stated that they had sufficient information (resources) for adequate treatment decision making. Among all physicians, 44% stated that there was insufficient knowledge within their institute regarding this topic. Only 17% stated that there was a multidisciplinary protocol available. The application of radiotherapy treatment adaptations (technique, dose, fractionation, field size) varied widely. Generally, there seemed to be no consensus regarding the expected toxicity of combined drug-radiotherapy treatments and the expected risk of tumor flare upon temporary drug discontinuation., Conclusion: There is no consensus amongst involved medical specialties on expected toxicity. Consequently, it is necessary to perform clinical studies examining the safety of combined drug-radiotherapy treatments, to add radiotherapy to phase I-III clinical trials for new drugs and to incorporate outcomes into multidisciplinary, evidence-based guidelines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Overall survival (OS) data of osimertinib in pretreated non-small-cell lung cancer (NSCLC) in real-world practice is limited, and treatment benefits for patients not represented in the pivotal trials (ineligible) are unclear., Objective: To determine the representativeness of the AURA3 trial for NSCLC patients treated with osimertinib in a real-world setting and to determine outcomes of patients who were represented in the AURA3 trial (eligible) and those who were ineligible., Methods: Advanced NSCLC patients receiving post first-line osimertinib were included in this retrospective study and were divided into two groups based on eligibility criteria of the AURA3 trial. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Cox models were used to estimate the association of eligibility criteria with OS., Results: 328 patients were included; 126 (38%) patients were eligible and 202 (62%) patients were ineligible. The most common ineligibility reasons were the number of earlier treatment lines and an Eastern Cooperative Oncology Group performance status (ECOG PS) > 1. PFS of eligible and ineligible patients was not statistically different (8.0 vs. 5.8 months, p = 0.062). Eligible patients had a longer OS (24.0 vs. 15.4 months, p = 0.001) compared to ineligible patients. ECOG PS was the best predictor for OS. An ECOG PS of 1 was already associated with poorer survival compared to an ECOG PS of 0 (hazard ratio 1.54; p = 0.016)., Conclusion: The majority of the study population was not represented in the AURA3 trial. Survival outcomes of eligible patients are in concordance with the AURA3 trial, while OS of ineligible patients was significantly shorter compared to eligible patients., (© 2021. The Author(s).)

Objectives: Patients with advanced stage non-small cell lung cancer (NSCLC) are generally considered incurable. The mainstay of treatment for these patients is systemic therapy. The addition of local treatment, including surgery, remains controversial. Oligoprogression is defined as advanced stage NSCLC with limited progression of disease after a period of prolonged disease stabilisation or after a partial or complete response on systemic therapy. In this retrospective study we evaluated outcome and survival of patients who underwent a resection for oligoprogression after systemic therapy for advanced stage NSCLC., Materials and Methods: Patients with oligoprogression after systemic treatment for advanced NSCLC who were operated in the Antoni van Leeuwenhoek Hospital were included. Patient and treatment characteristics were collected in relation to progression free survival (PFS) and overall survival (OS)., Results: Between January 2015 and December 2019, 28 patients underwent surgery for an oligoprogressive lesion (primary tumor lung (n = 12), other metastatic site (n = 16)). Median age at time of resection was 60 years (39-86) and 57% were female. Postoperative complications were observed in 2 patients (7%). Progression of disease after resection of the oligoprogressive site was observed in 17 patients (61%). Median PFS was 7 months since date of resection (95% CI 6.0-25.0) and median OS was not reached. Seven patients (25%) died during follow-up. Age was predictive for OS and clinical T4 stage was predictive for PFS. M1 disease at initial presentation was predictive for better PFS compared to patients who were diagnosed with M0 disease initially. Patients who underwent resection because of oligoprogression of the primary lung tumour had a better PFS, when compared to oligoprogression of another metastastic site., Conclusion: Surgical resection of an oligoprogressive lesion in patients with advanced NSCLC treated with systemic treatment is feasible and might be considered in order to achieve long term survival., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important-and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendations for optimal molecular diagnostics in the post-EGFR tyrosine kinase inhibitor (TKI) resistance setting., Methods: We compared molecular workup strategies from three hospitals of 161 first- or second-generation EGFR TKI-treated cases and 159 osimertinib-treated cases. Laboratories used combinations of DNA next-generation sequencing (NGS), RNA NGS, in situ hybridization (ISH), and immunohistochemistry (IHC)., Results: Resistance mechanisms were identified in 72 first-generation TKI cases (51%) and 85 osimertinib cases (57%). RNA NGS, when performed, revealed fusions or exon-skipping events in 4% of early TKI cases and 10% of osimertinib cases. Of the 30 MET and HER2 amplifications, 10 were exclusively detected by ISH or IHC, and not detected by DNA NGS, mostly owing to low tumor cell percentage (<30%) and possibly tumor heterogeneity., Conclusions: Our real-world data support a method for molecular diagnostics, consisting of a parallel combination of DNA NGS, RNA NGS, MET ISH, and either HER2 ISH or IHC. Combining RNA and DNA isolation into one step limits dropout rates. In case of financial or tissue limitations, a sequential approach is justifiable, in which RNA NGS is only performed in case no resistance mechanisms are identified. Yet, this is suboptimal as-although rare-multiple acquired resistance mechanisms may occur., (© 2021 THE AUTHORS.)

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments., Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety., Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves., Competing Interests: Disclosure H Yu has received research funding to her institution from AstraZeneca, Pfizer, Cullinan, Daiichi, Novartis, Lilly and advisory board fees from AstraZeneca, Blueprint Medicine and Janssen. S Goldberg has received research funding from AstraZeneca and Boehringer Ingelheim, received advisory board/personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech and Spectrum. Z Piotrowska has received research funding to her institution from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro, Cullinan, Daiichi and AbbVie and has received advisory board fees from AstraZeneca, Blueprint Medicines, Janssen, Takeda, Jazz Pharmaceuticals and C4 Therapeutics. X Le receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Eli Lilly, Boehringer Ingelheim, and Research Funding from Eli Lilly and Boehringer Ingelheim. JW Riess has received research funding from AstraZeneca, Merck, Spectrum, Revolution Medicines and Novartis, received advisory board/personal fees from Novartis, Medtronic, Blueprint Medicines, Boehringer Ingelheim and Spectrum. G Patel is an employee of AstraZeneca. H Ambrose, J Chmielecki, G Doughton, S Kraljevic, X Li-Sucholeiki, J Maidment and P Szekeres are employees of AstraZeneca and hold stock/stock options., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands., Materials and Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy., Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type-specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%)., Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a "Dutch MTB model" for an optimal, collaborative, and nationally aligned MTB workflow., Implications for Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

In multiple malignancies, checkpoint inhibitor therapy has an established role in the first-line treatment setting. However, only a subset of patients benefit from checkpoint inhibition, and as a result, the field of biomarker research is active. Molecular imaging with the use of positron emission tomography (PET) is one of the biomarkers that is being studied. PET tracers such as conventional 18 F-FDG but also PD-(L)1 directed tracers are being evaluated for their predictive power. Furthermore, the use of artificial intelligence is under evaluation for the purpose of response prediction. Response evaluation during checkpoint inhibitor therapy can be challenging due to the different response patterns that can be observed compared to traditional chemotherapy. The additional information provided by PET can potentially be of value to evaluate a response early after the start of treatment and provide the clinician with important information about the efficacy of immunotherapy. Furthermore, the use of PET to stratify between patients with a complete response and those with a residual disease can potentially guide clinicians to identify patients for which immunotherapy can be discontinued and patients for whom the treatment needs to be escalated. This review provides an overview of the use of positron emission tomography (PET) to predict and evaluate treatment response to immunotherapy.